2,6-Methano-3-benzazocines

ABSTRACT

6(eq)-R4-1,2,3,4,5,6-Hexahydro-3-R1-11(ax)-R3-11(eq)-CH2Z-2,6-methano- 3-benzazocines, useful as analgesic agents and narcotic antagonists, prepared by heating, with formic acid in an organic solvent or with certain ammonium formates in the absence of a solvent, certain 1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolines.

RELATED APPLICATIONS

This is a division of my prior, copending application Ser. No. 9,594,filed Feb. 5, 1979, now U.S. Pat. No. 4,255,579, patented Mar. 10, 1981,which is a continuation-in-part of my prior application Ser. No.877,166, filed Feb. 13, 1978, now U.S. Pat. No. 4,180,667, patented Dec.25, 1979, which in turn is a continuation-in-part of my priorapplication Ser. No. 741,227, filed Nov. 12, 1976, now U.S. Pat. No.4,100,164, patented July 11, 1978, which in turn is acontinuation-in-part of my prior, now abandoned application Ser. No.695,977, filed June 14, 1976, which in turn is a continuation-in-part ofmy prior, now abandoned application Ser. No. 576,313, filed May 12,1975, which in turn is a continuation-in-part of my prior applicationSer. No. 471,571, filed May 20, 1974, now U.S. Pat. No. 3,932,422,patented Jan. 13, 1976.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to 11(eq)-substituted-2,6-methano-3-benzazocinesuseful as analgesics and narcotic antagonists.

(b) Description of the Prior Art

2,6-Methano-3-benzazocines substituted in the 11-position with alower-alkyl group are known. (See for example Gordon et al. U.S. Pat.No. 2,924,603, patented Feb. 9, 1960). Moreover, it is known thatcompounds in the 5,14-endo-etheno- and ethanotetrahydrooripavine serieshaving ketone, carbinol or lower-alkenyl groups at the 7-positionthereof have unusual analgesic potency relative to morphine. [SeeBentley et al., J. Am. Chem. Soc. 89, 3267-3292 (1967)]. Consequentlythere has been much interest in the field of analgesics in incorporatingthe ketone, carbinol or lower-alkenyl function present in the latterseries at the 11-position of 2,6-methano-3-benzazocine-type analgesics,but all synthetic efforts in this direction have previously beenunsuccessful.

Certain species of 8-R₂ -9-R₂ '-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁-11(ax)-R₃ -11(eq)-CH₂ Z-2,6-methano-3-benzazocines where R₂ representsa variety of substituents, not including methoxymethoxy; Z representsvarious ketone functions, CH₂ COR₅, but not including the oxime orcarboxymethyloxime thereof, and where R₅ is other than cyclo-lower-alkylor either phenyl or phenyl-lower-alkyl substituted in either case in thephenyl ring thereof by a variety of simple substituents; and where Zalso represents ##STR1## but not the isomeric group ##STR2## (where R₅is lower-alkyl and R₆ ' and R₈ are hydrogen or lower-alkyl), aredisclosed in my Japanese Patent Appln. 60,111/75, filed May 20, 1975,published Dec. 25, 1975, with corresponding identical disclosure in myU.S. Pat. No. 3,932,422, patented Jan. 13, 1976.

SUMMARY OF THE INVENTION

In a composition of matter aspect, the invention relates to certain 7-R₂"-8-R₂ -9-R₂ '-10-R₂ "'-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃-11(eq)-CH₂ Z-2,6-methano-3-benzazocines, where Z is a ketone, carbinolor lower-alkenyl function and R₁, R₂, R₂ ', R₂ ", R₂ "', R₃ and R₄ arehydrogen, lower-alkyl or other organic groups more specifically definedhereinafter, which are useful as analgesics and narcotic antagonists.

In a process aspect, the invention relates to a process for preparingcertain 7-R₂ "-8-R₂ -9-R₂ '-10-R₂ "'-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂ Z-2,6-methano-3-benzazocinescomprising heating, with formic acid in an inert organic solvent or witha benzyl-di-lower-alkylammonium formate or a tri-lower-alkylammoniumformate, certain 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ "'-1-R₁ -3-Y-4aα-R₃ -5α-R₄-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolines.

DETAILED DESCRIPTION INCLUSIVE OF THE PREFERRED EMBODIMENTS

More specifically this invention has, as its ultimate object, theobtainment of a new class of chemical compounds, useful as analgesicsand narcotic antagonists, having the formula I: ##STR3## and chemicallydesignated 7-R₂ "-8-R₂ -9-R₂ '-10-R₂ "'-6(eq)-R₂-1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂Z-2,6-methano-3-benzazocines.

The new 7-R₂ "-8-R₂ -9-R₂ '-10-R₂ "-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁-11(ax)-R₃ -11(eq)-CH₂ Z-2,6-methano-3-benzazocines of formula I andother novel intermediates useful in their preparation are obtainedaccording to my invention by novel reactions, including molecularrearrangements involving novel intermediates, according to the generalreaction sequence as follows: ##STR4##

Thus the 7-R₂ "-8-R₂ -9-R₂ '-10-R₂ "'-6(eq)-R₄-1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂Z-2,6-methano-3-benzazocines having the formula I are prepared via anyof several methods from the intermediate 6-R₂ "-7-R₂ -8-R₂ '-9-R₂"'-1-R₁ -3-Y-3-R₈ -4aα-R₃ -5α-R₄-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolines of formulaII, which themselves are obtained from the 2-R₁ -3-(4-R₂ -3-R₂ "[or 5-R₂]-6-R₂ "'-benzyl)-4-R₃ -5-R₄ -7-Y'-2-azabicyclo[2.2.2]-oct-5-enes offormula IV which, in turn, are prepared according to standard proceduresby reaction of a Grignard reagent derived from a 4-R₂ -3-R₂ '- (or R₂")-2-R₂ "'-benzyl halide of formula VI with a 3-R₃ -4-R₄ -1-R₁-pyridinium halide of formula VII and reaction of the resulting 1-R₁-2-(4-R₂ -3-R₂ '[or R₂ "]-2-R₂ "'-benzyl)-3-R₃ -4-R₄ -1,2-dihydropyridine of formula VIII with a dienophile, CH₂ ═CHY'. The 6-R₂"-7-R₂ -8-R₂ '-9-R₂ "'-1-R₁ -2-Q-4aα-R₃ -5α-R₄-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinolines of formulaIIIa are obtained along with certain compounds of formula I from thecompounds of formula II where Y is COR₅ and R₈ is hydrogen.

In the final products and intermediates depicted in the above reactionsequences:

R₁ is hydrogen, lower-alkyl, lower-alkanoyl (only when R₄ is hydrogen),lower-alkenyl, lower-alkynyl, halo-lower-alkenyl, cyclo-lower-alkyl,cyclo-lower-alkyl-lower-alkyl, 2- or 3-furylmethyl, or such 2- or3-furylmethyl substituted on the unsubstituted ring carbon atoms by fromone to three methyl groups, phenyl-lower-alkyl, or phenyl-lower-alkylsubstituted in the phenyl ring by from one to two members of the groupconsisting of halogen (including bromine, chlorine and fluorine),lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy,lower-alkylmercapto, trifluoromethyl, amino, lower-alkanoylamino or asingle methylenedioxy attached to adjacent carbon atoms;

R₂, R₂ ' R₂ ", and R₂ "' are each hydrogen, or three of them arehydrogen and the fourth is halogen (including bromine, chlorine orfluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy,lower-alkylmercapto, trifluoromethyl, nitro, amino, lower-alkanoylamino,lower-alkoxycarbonylamino or phenyl, or two of the adjacent such groupstogether are methylenedioxy;

R₃ is hydrogen or lower-alkyl;

R₄ is hydrogen, lower-alkyl, lower-alkoxy-lower-alkyl,hydroxy-lower-alkyl, lower-alkylthio-lower-alkyl,lower-alkylsulfinyl-lower-alkyl, phenylthio-lower-alkyl,phenylsulfinyl-lower-alkyl, lower-alkenyl or halo-lower-alkyl, or R₃ andR₄ together are divalent lower-alkylene, --(CH₂)_(n) --, where n is oneof the integers 3 or 4;

Z is one of the groups ##STR5## or the ethylene glycol ketal thereof,##STR6## or a group of the formula: ##STR7##

R₅ and R₆ are the same or different hydrogen, lower-alkyl,cyclo-lower-alkyl-lower-alkyl, phenyl or phenyl-lower-alkyl;

R₇ is hydrogen, lower-alkanoyl, benzoyl, or benzoyl substituted by fromone to three members of the group consisting of lower-alkyl,lower-alkoxy, hydroxy, halo (including chlorine, bromine and fluorine)or trifluoromethyl;

R₈ is hydrogen or lower-alkyl;

Y is carboxy, cyano, carbo-lower-alkoxy, COR₅,COO-lower-alkylene-cyclo-lower-alkyl, COO-lower-alkylene-phenyl, or agroup of the formula: ##STR8##

Y' is carboxy, cyano, carbo-lower-alkoxy,COO-lower-alkylene-cyclo-lower-alkyl, COO-lower-alkylene-phenyl orlower-alkanoyl; and Hal is halogen.

Also within the purview of the invention are compounds of formula Iwhere R₁, R₃ and R₄ are each lower-alkyl; R₂ is hydrogen, hydroxy ormethoxymethoxy (only when Z is CH₂ COR₅ and R₅ is lower-alkyl); R₂ ', R₂" and R₂ "' are each hydrogen; and Z is either (a) the oxime orO-carboxymethyloxime (═NOCH₂ COOH) of a compound where Z is CH₂ COR₅,where R₅ is lower-alkyl; (b) CH₂ COR₅, where R₅ is cyclo-lower-alkyl;(c) CH₂ COR₅, where R₅ is either phenyl or phenyl-lower-alkylsubstituted in either case in the phenyl ring by from one to two membersof the group consisting of lower-alkyl, lower-alkoxy,lower-alkylmercapto, trifluoromethyl or methylenedioxy attached toadjacent carbon atoms; or (d) the group ##STR9## where R₅ islower-alkyl, R₆ ' is hydrogen or lower-alkyl and R₈ is hydrogen orlower-alkyl.

As used herein, the terms lower-alkyl or lower-alkoxy means saturated,acyclic groups which may be straight or branched containing from one toabout seven carbon atoms as exemplified by methyl, ethyl, propyl,isopropyl, butyl, nonadjacent t-butyl, methoxy, ethoxy, propoxy,isopropoxy, or t-butoxy.

As used herein, the terms lower-alkenyl, halo-lower-alkenyl andlower-alkynyl represent monovalent groups of from three to seven carbonatoms containing one double or triple bond as illustrated, for example,by 1-propenyl, 2-butenyl, 4-pentenyl, 3-methyl-2-butenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-propynyl, 2-butynyl,4-pentynyl, 2-hexynyl, and the like. The term halo-lower-alkenylincludes, for example, 2-chloroethenyl, 2-bromoethenyl,3,3-dichloro-2-propenyl, 1-bromo-2-methylpropenyl, and the like.

As used herein, the term cyclo-lower-alkyl means saturated carbocyclicgroups containing from three to seven ring carbon atoms as illustrated,for example, by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2-methylcyclobutyl, 4-ethylcyclohexyl, and the like.

As used herein, the term lower-alkanoyl means such groups derived fromsaturated, aliphatic monocarboxylic acids having from one to four carbonatoms, as illustrated, for example, by formyl, acetyl, propionyl,butyryl, isobutyryl, and the like.

As used herein, the term lower-alkylene means a saturated, divalentradical, which can be straight or branched, and having from one to fourcarbon atoms, as illustrated, for example, by methylene [--CH₂ --],1,2-ethylene [--CH₂ CH₂ --], 1,3-propylene [--CH₂ CH₂ CH₂ ],1,2-(1-methylethylene) [--CH(CH₃)CH₂ --], 1,4-butylene [--CH₂ CH₂ CH₂CH₂ --], and the like.

As determined by standard pharmacological test procedures to bedescribed hereinafter, the compounds of formula I have been found tohave useful analgesic activity, and as indicated by pharmacological testdata presented hereinafter, some compounds of formula I have also beenfound to have useful narcotic antagonist activity. The compounds offormula I are thus useful as analgesic agents and narcotic antagonists.

Preferred compounds within the ambit of formula I are those where Z isthe group CH₂ COR₅ where R₅ is lower-alkyl,cyclo-lower-alkyl-lower-alkyl or phenyl-lower-alkyl, and R₁, R₂, R₂ ',R₂ ", R₂ "', R₃ and R₄ have the meanings given above, and particularlypreferred compounds are those of the latter type where R₁, R₃ and R₄ areeach lower-alkyl; R₂ is hydroxy; and R₂ ', R₂ " and R₂ "' are eachhydrogen.

In accordance with the above general description, the 7-R₂ "-8-R₂ -9-R₂'-10-R₂ "'-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂Z-2,6-methano-3-benzazocines of formula I where Z is ##STR10## and R₁,R₂, R₂ ', R₂ ", R₂ "', R₃, R₄, R₅, R₆ and R₈ have the meanings givenabove are prepared by heating, with formic acid in an organic solvent,for example toluene, xylene or mesitylene, or with abenzyl-di-lower-alkylammonium or a tri-lower-alkylammonium formate at atemperature in the ring from 120°-150° C., a 6-R₂ "-7-R₂ -8-R₂ '-9-R₂"'-1-R₁ -3-Y-3-R₈ -4aα-R₃ -5α-R₄-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline of formulaII where R₈ is hydrogen and Y is either COR₅ (to give the compounds offormula I where Z is CH₂ COR₅) or the group: ##STR11## where R₇ ishydrogen (to give the compounds of formula I where Z is ##STR12## Apreferred solvent is mesitylene. The compounds of formula II where Y isCOR₅ or the group ##STR13## where R₇ is hydrogen are thus intermediatesfor preparing the compounds of formula I where Z is, repsectively, thegroups --CH₂ COR₅ or ##STR14##

The compounds of formula I where R₅ is benzyl (or benzyl substituted inthe phenyl ring thereof by the substituents enumerated above) and R₁,R₂, R₂ ', R₂ ", R₂ "', R₃, R₄, R₆ and R₈ have the meanings given abovecan also be prepared by reaction of a lower-alkyl β-[7-R₂ "-8-R₂ -9-R₂'-10-R₂ "'-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃-2,6-methano-3-benzazocin-11(eq)-yl]-propionate of formula Ia with analkali metal salt of phenylacetic acid (or a phenylacetic acidsubstituted in the phenyl ring thereof), the latter prepared by reactionof the desired phenylacetic acid with two molar equivalents of an alkalimetal amide, followed by hydrolysis and simultaneous decarboxylation ofthe resulting condensation product. The method is illustrated by thereaction using unsubstituted phenylacetic acid: ##STR15## where Alkrepresents lower-alkyl. The esters of formula Ia and the method fortheir preparation are disclosed in Lewis and Michne U.S. Pat. No.4,119,628, patented Oct. 10, 1978, and c.i.p. thereof U.S. Pat. No.4,148,794, which applications are more fully described below, thedisclosures of which are incorporated herein by reference.

The oximes or O-carboxymethyloximes of the compounds of formula I whereZ is ##STR16## are prepared by reacting the latter with hydroxylamine orO-carboxymethylhydroxylamine in an inert organic solvent, for example alower-alkanol. The reaction is carried out by heating the reactants inthe solvent at the reflux temperature of the latter.

The compounds of formula I where Z is ##STR17## where R₈ is lower-alkyl,are prepared by treatment of the compounds of formula IIB, where R₈ ishydrogen and Y is a proton activating group, i.e. an ester or keto(COR₅) group, with a strong base, for example a lithiumdi-lower-alkylamide, a preferred base being lithium diisopropylamide,and reaction of the resulting lithium salt with a lower-alkyl ester of astrong mineral acid, for example a lower-alkyl halide or adi-lower-alkyl sulfate. The ester or keto group Y in the compounds offormula IIA thus obtained can then be converted to other groups, forexample ##STR18## before conversion of the latter to the compounds offormula I where Z is ##STR19## and R₈ is lower-alkyl by heating thecompounds of formula II where R₈ is lower-alkyl with formic acid in anorganic solvent or with a benzyl-di-lower-alkylammonium ortri-lower-alkylammonium formate as described above.

As indicated in the above reaction sequence, alkylation of the compoundsof formula IIB via the lithium salt results in epimerization of the Ygroup. It had been previously thought that the group Y in the compoundsof formula IIB as obtained by cyclization of the compounds of formula IVpossesses the β-configuration, i.e. the group Y is cis to the2,5-methano bridge (vide infra), and such steric configuration of thegroup Y is disclosed in Sterling Drug Inc.-owned Japanese ProvisionalPatent Publication No. 160,275, published Dec. 26, 1976 from JapanesePatent Appln. 60,111/75, filed May 20, 1975 as well as in U.S. Pat. No.3,932,422, patented Jan. 13, 1976 on application Ser. No. 471,571, filedMay 20, 1974 and on which Japanese Appln. 60,111/75 was based. However,since the time of preparation and filing of the Japanese application onwhich the patent publication is based, some uncertainty has developedover whether the group Y has the α- or β-configuration. In any event,alkylation of the compounds of formula IIB via the lithium salt resultsin epimerization of the group Y, and in fact, the compounds of formulaIIA where R₈ is hydrogen and the Y group is in either the α- or theβ-configuration can be prepared from the respective β-Y or α-Y compoundsby treatment first with a strong base and then with acid. In view of thefact then that either of the groups Y and R₈ in the compounds offormulas IIA and IIB, respectively, can occupy either the α- or theβ-configuration, the compounds of formulas IIA and IIB can be generallyrepresented by the formula: ##STR20## where R₈ is hydrogen orlower-alkyl.

Insofar as the structures of the 2,6-methano-3-benzazocines of formula Iare concerned, the question of the steric configuration at the3-position of the compounds of formula II is moot, because the asymmetryat the 3-position is destroyed on conversion of the compounds of formulaII to the compounds of formula I, and the compounds of formula II havingboth possible steric configurations at the 3-position are fully operablefor the preparation of the compounds of formula I.

Insofar as the steric configuration of the group Q in the compounds offormula IIIa is concerned, a study of molecular models of hypotheticalreaction intermediates indicates that the group Q probably has theβ-configuration, i.e. Q is cis to the 3,5-etheno bridge, but theconfiguration has not been rigorously established.

The compounds of formula I where Z is the group: ##STR21## where R₇ ishydrogen and R₅, R₆ and R₈ have the meanings given above are preparedfrom the corresponding compounds where Z is the group ##STR22## byhydroxylation of the latter, for example with concentrated sulfuric acidand hydrolysis of the resulting hydrogen sulfate ester. The compounds offormula I where Z is the group ##STR23## are thus intermediates for thecarbinols of formula I.

The compounds of formula I where Z is the group ##STR24## where each ofR₆ and R₇ is hydrogen and R₅ and R₈ have the meanings given above areprepared by selective reduction of the corresponding compounds where Zis ##STR25## When R₅ is hydrogen the selective reduction is carried outwith an alkali metal aluminum hydride in an inert organic solvent suchas dioxane, tetrahydrofuran or diethyl ether at temperatures in therange from about 0° C. to 100° C. When R₅ is lower-alkyl,cyclo-lower-alkyl-lower-alkyl, phenyl or phenyl-lower-alkyl, thereduction is carried out with an alkali metal borohydride in an inertorganic solvent, for example lower-alkanols, such as methanol, ethanolor isopropanol.

The compounds of formula I where Z is ##STR26## R₅ and R₆ are eachlower-alkyl, cyclo-lower-alkyl, cyclo-lower-alkyl-lower-alkyl, phenyl,phenyl-lower-alkyl, or substituted-phenyl or phenyl-lower-alkyl, R₇ ishydrogen and R₈ is hydrogen or lower-alkyl are prepared by reaction ofthe corresponding compounds where Z is ##STR27## where R₅ islower-alkyl, cyclo-lower-alkyl, cyclo-lower-alkyl-lower-alkyl, phenyl,phenyl-lower-alkyl or substituted-phenyl or phenyl-lower-alkyl with onemolar equivalent of an appropriate organo lithium, R₆ Li, where R₆ hasthe meanings given above. The reaction is carried out in an inertorganic solvent such as benzene or toluene. In this manner compoundswhere R₅ and R₆ are either the same or different lower-alkyl,cyclo-lower-alkyl, cyclo-lower-alkyl-lower-alkyl, phenyl,phenyl-lower-alkyl, or substituted phenyl or phenyl-lower-alkyl groupscan be prepared depending upon the identity of the R₅ group and thechoice of the particular organo lithium.

The compounds of formula I where Z is ##STR28## are prepared from thecorresponding compounds where Z is ##STR29## by use of the Wittigreaction which comprises reacting the latter with a lower-alkylidenetriphenylphosphorane, the latter prepared by reaction of a lower-alkyltriphenyl phosphonium halide with an alkali metal hydride, in an inertorganic solvent, for example dimethylsulfoxide, as illustrated by thereaction sequence where Bz represents the11-(hexahydro-2,6-methano-3-benzazocinyl) portion of formula I:##STR30##

The compounds of formula I where Z is ##STR31## where R₅, R₆ ' and R₈have the meanings given above are prepared by dehydration, under acidconditions, of the corresponding carbinol where Z is the group ##STR32##where R₆ is lower-alkyl, the compounds of formula I where R₆ ismethylene (═CH₂) being of course produced when R₆ is methyl. Suitableacid media for dehydration are sulfuric acid or acetic acid incombination with a strong organic or inorganic acid, for examplemethanesulfonic acid.

Neither of the two above-described processes for preparing the compoundsof formula I where Z is ##STR33## are disclosed in my above-identifiedJapanese Patent Application 60,111/76 or U.S. Pat. No. 3,932,422. Infact the process disclosed in those prior publications for preparingcompounds of formula I where Z is ##STR34## is inoperative for thepreparation of the compounds where Z is the group ##STR35##

The compounds of formula I where Z is ##STR36## R₅ and R₆ are eachhydrogen or the same or different lower-alkyl, cycloalkyl,cycloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl or substituted phenylor phenyl-lower-alkyl, R₈ has the meanings given above, and R₇ islower-alkanoyl, benzoyl or substituted-benzoyl are prepared byesterification of the corresponding compounds where R₇ is hydrogen, forexample with an appropriate acid halide, anhydride or other acylatingagent. The reaction is advantageously carried out using an appropriateacid halide in a pyridine solvent which serves as an acid-acceptor totake up the hydrogen halide split out during the course of the reaction.

The compounds of formula I where R₁ is lower-alkenyl, lower-alkynyl,halo-lower-alkenyl or 2- or 3-furylmethyl (or such 2- or 3-furylmethylsubstituted by from one to three methyl groups) are advantageouslyprepared from the corresponding compounds where R₁ is hydrogen byreaction of the latter with an appropriate lower-alkenyl halide,lower-alkynyl halide or halo-lower-alkenyl halide, as the case may be,in an inert organic solvent, for example a lower-alkanol, acetone ordimethylformamide (hereinafter designated DMF), in the presence of anacid-acceptor, for example an alkali metal carbonate or bicarbonate. Apreferred solvent is DMF.

The compounds of formula I where R₂, R₂ ', R₂ " or R₂ '" islower-alkanoyloxy are advantageously prepared from the correspondingcompounds where R₂, R₂ ', R₂ " or R₂ '" is hydroxy by esterificationwith an appropriate lower-alkanoyl halide in the presence of pyridine.

The compounds of formula I where R₂, R₂ ', R₂ " or R₂ '" is amino areprepared by hydrolysis of the corresponding compounds where R₂, R₂ ', R₂" or R₂ '" is lower-alkanoylamino or lower-alkoxycarbonylamino byheating the latter in aqueous alkali.

Alternatively, the compounds of formula I where R₂, R₂ ', R₂ " or R₂ '"is amino are prepared by reaction of the compounds of formula I where Zis ##STR37## and R₁ is hydrogen with nitric acid in glacial acetic acid.The reaction is carried out at temperatures from 0° to 5° C. Theresulting nitro compound is then alkylated as desired in the mannerdescribed above to prepare compounds where R₁ has the other variousmeanings given above, and in a final step, the nitro group is reduced tothe corresponding amino group by either catalytic means, for examplewith hydrogen over palladium-on-charcoal, or by chemical means, forexample by iron and hydrochloric acid or by tin and hydrochloric acid.

The compounds of formula I where R₂ is methoxymethoxy are prepared byreaction of the corresponding compounds where R₂ is hydroxy withdimethoxymethane in the presence of a catalytic amount of a strong acidand in an inert organic solvent. The reaction is carried out byrefluxing a solution of the reactants in the chosen solvent, for examplechloroform, methylene dichloride, ethylene dichloride and the like,under a Soxhlet extractor containing molecular sieves having a pore sizesufficient to trap and hold molecules of methanol.

In this way the methanol produced in the reversible reaction is removedfrom the reaction mixture as it is formed, and the reaction proceeds tocompletion. It has been found that 4A molecular sieves have a porosityof the proper size for this purpose.

The compounds of formula I where R₂ is methoxymethoxy are particularlyuseful as intermediates for preparing the corresponding compounds whereR₂ is hydroxy and which contain acid sensitive groups elsewhere in themolecule, for example compounds where Z is CH₂ COR₅ where R₅ iscyclopropyl, since the methoxymethoxy group is readily cleaved undermild acid conditions.

As indicated in the reaction sequence shown above, the 6-R₂ "-7-R₂ -8-R₂"'-9-R₂ "'-1-R₁ -2-Q-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinolines of formula IIIa where Q isH₂, CH-lower-alkyl, CH-cyclo-lower-alkyl, CH-cyclo-lower-alkyllower-alkyl, CH-phenyl, CH-lower-alkylphenyl, or substituted CH-phenylor CH-lower-alkylphenyl are produced along with the compounds of formulaI (where Z is --CH₂ COR₅) when the compounds of formula II where Y isCOR₅ and R₈ is hydrogen are heated with formic acid in an organicsolvent or with a benzyl-di-lower-alkylammonium formate or atri-lower-alkylammonium formate as described above. When thebenzazocines of formula I are the desired product, it is preferred tocarry out the reaction in mesitylene using a concentration of 0.05 molarin starting material of formula II and 1.0 molar in formic acid. Thismixture gives a reaction temperature at reflux of about 120° C. andaffords the benzazocines of formula I and the benzo[g]-quinolines offormula IIIa in a ratio of from 2:1 to 3:1. By progressively decreasingthe formic acid concentration, successively higher boiling mixtures areproduced, which result in production of progressively increased relativeamounts of the benzo[g]quinolines. Thus at formic acid concentration of0.5 molar and 0.15 molar (0.05 molar in starting material), thebenzo[g]-quinolines and benzazocines are produced in ratios of about 2:1and 7:1, respectively. Similarly, by using a ratio of 1 mole of startingmaterial to 5 moles of, respectively, benzyldimethylammonium formate ortrimethylammonium formate or triethylammonium formate and heating themixture (in the absence of any organic solvent) at 150° C. for aboutfifteen minutes, a mixture of benzo[g]-quinoline and benzazocine isproduced in ratios of 10:1, 3:1 and 20:1, respectively.

The two transformations thus take place simultaneously under the givenconditions and are best seen by reference to the reaction sequence:##STR38## where R₁, R₂, R₂ ', R₂ ", R₂ "', R₃, R₄, R₅, R₈ and Q have themeanings given above. It will be seen from the above that the compoundsof formula I result by rupture, under the reaction conditions, of bond(b) in the compounds of formula II, whereas the compounds of formulaIIIa result when bond (a) is broken, followed by ring closure betweenthe nitrogen atom and the carbonyl group of the COR₅ moiety.

An alternative process for preparing the compounds of formula I whichdoes not result in production of compounds of formula IIIa is theprocess described in T. R. Lewis and W. F. Michne U.S. Pat. No.4,119,628, the disclosure of which is incorporated herein by reference,which is useful for the preparation of the compounds of formula I when Zis ##STR39## where R₈ is hydrogen and R₅ has all the meanings givenabove. According to the Lewis and Michne process, a lower-alkyl 1-R₁-3-R₅ CO-4aα-R₃ -5α-R₄ -6-R₂ "-7-R₂ -8-R₂ '-9-R₂'"1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylatehaving the formula IX is heated with formic acid in an inert organicsolvent, for example toluene, xylene, or mesitylene, or with abenzyl-di-lower-alkylammonium formate or a tri-lower-alkylammoniumformate using the same conditions as described above for the conversionof the compounds of formula II to the compounds of formula I. Thereaction results in simultaneous ring opening between the carbon atomsat the 2- and 3-positions of the compounds of formula IX and hydrolysisand decarboxylation of the 3-carbo-lower-alkoxy group, COOALk, accordingto the following reaction: ##STR40## where R₁, R₂, R₂ ', R₂ ", R₂ "',R₃, R₄ and R₅ have the meanings given above, and Alk representslower-alkyl.

The compounds of formula IX and the methods for their preparation aredescribed in the above-identified Lewis and Michne U.S. Pat. No.4,119,628.

The compounds of formulas II, IIA, IIB, IIIa and IV, and methods fortheir preparation are described in detail in U.S. Pat. Nos. 3,932,422and 4,100,164 and in the parent application hereof, Ser. No. 877,166,now U.S. Pat. No. 4,180,667, the disclosures of all of which areincorporated herein by reference.

The compounds of formula I where R₁ is benzyl can be catalyticallydebenzylated to give the corresponding compounds where R₁ is hydrogen.The latter can then be realkylated with an appropriate alkylating agentto give other different compounds where R₁ has the meanings, other thanhydrogen, given above. Reduction is carried out in an inert organicsolvent, for example ethanol, isopropanol, and the like, and atpressures from 40 to 100 p.s.i.g. A preferred catalyst ispalladium-on-charcoal. The alkylation of the compounds of formula Iwhere R₁ is hydrogen is carried out in an inert organic solvent, forexample acetone, ethanol or DMF, and in the presence of anacid-acceptor, for example alkali metal carbonates or bicarbonates.

Due to the presence of a basic amino grouping, the free base formsrepresented by formula I react with organic and inorganic acids to formacid-addition salts. The acid-addition salt forms are prepared from anyorganic or inorganic acid. They are obtained in conventional fashion,for instance either by direct mixing of the base with the acid or, whenthis is not appropriate, by dissolving either or both of the base andthe acid separately in water or an organic solvent and mixing the twosolutions, or by dissolving both the base and the acid together in asolvent. The resulting acid-addition salt is isolated by filtration, ifit is insoluble in the reaction medium, or by evaporation of thereaction medium to leave the acid-addition salt as a residue. The acidmoieties or anions in these salt forms are in themselves neither novelnor critical and therefore can be any acid anion or acid-like substancecapable of salt formation with the base.

Representative acids for the formation of the acid-addition saltsinclude formic acid, acetic acid, isobutyric acid,alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaricacid, succinic acid, succinamic acid, tannic acid, glutamic acid,tartaric acid, oxalic acid, pyromucic acid, citric acid, lactic acid,glycolic acid, gluconic acid, saccharic acid, ascorbic acid, penicillin,benzoic acid, phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid,anthranilic acid, cholic acid, 2-pyridinecarboxylic acid, pamoic acid,3-hydroxy-2-naphthoic acid, picric acid, quinic acid, tropic acid,3-indoleacetic acid, barbituric acid, sulfamic acid, methanesulfonicacid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid,p-toluenesulfonic acid, butylarsonic acid, methanephosphonic acid,acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid,hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoricacid, arsenic acid, and the like.

All of the acid-addition salts are useful as sources of the free baseforms, by reaction with an inorganic base. It will thus be appreciatedthat if one or more of the characteristics, such as solubility,molecular weight, physical appearance, toxicity, or the like of a givenbase or acid-addition salt thereof render that form unsuitable for thepurpose at hand, it can be readily converted to another, more suitableform. For pharmaceutical purposes, acid-addition salts of relativelynon-toxic, pharmaceutically-acceptable acids, for example hydrochloricacid, lactic acid, tartaric acid, and the like, are of course employed.

The compounds of this invention can exist in stereochemically isomericforms, that is, optical isomers and geometric isomers, and all suchisomers are considered to be within the purview of the invention. Ifdesired, the isolation or the production of a particular stereochemicalform can be accomplished by application of the general principles knownin the prior art. In the nomenclature employed for the compounds offormula I herein, "ax" stands for axial and "eq" for equatorial, and theconfigurations are given with reference to the hydroaromatic ring. Thus,the 6(eq), 11(ax) compounds of formula I are in the cis configuration,whereas the 6(eq), 11(eq) compounds are in the trans configuration.

In standard pharmacological test procedures, the compounds of formula Iand the acid-addition salts thereof have been found useful asdepressants of the central nervous system, and more particularly havebeen found useful as analgesics and as antagonists of strong analgesicssuch as phenazocine, meperidine and morphine.

The compounds of formula I can be administered in the same manner asknown analgesics and antagonists of strong analgesics, i.e. parenterallyor orally in any of the conventional pharmaceutical forms, as forinstance solutions, suspensions, tablets, capsules, and the like.

As described above, and as will be seen hereinbelow, many of the speciesof formula I are readily interconvertible by simple and well-knownreactions such as reduction, oxidation, hydrolysis, esterification,etherification, and the like, so that they are also useful asintermediates for each other.

The useful properties of the compounds of this invention weredemonstrated by standard pharmacological procedures readily carried outby technicians having ordinary skill in pharmacological test procedures,so that the actual determination of the numerical biological datadefinitive for a particular test compound can be ascertained without theneed for any extensive experimentation.

The test procedures used to determine the analgesic and analgesicantagonist activities of the compounds of the invention have beendescribed in detail in the prior art and are as follows: theacetylcholine-induced abdominal constriction test, which is a primaryanalgesic screening test designed to measure the ability of a test agentto suppress acetylcholine-induced abdominal constriction in mice,described by Collier et al., Brit. J. Pharmacol. Chemotherap. 32, 295(1968); a modification of the anti-bradykinin test, which is also aprimary analgesic screening procedure, described by Berkowitz et al., J.Pharmacol. Exp. Therap. 177, 500-508 (1971), Blane et al., J. Pharm.Pharmacol. 19, 367-373 (1967), Botha et al., Eur. J. Pharmacol. 6,312-321 (1969) and Deffenu et al., J. Pharm. Pharmacol. 18, 135 (1966);the phenyl-p-quinone-induced writhing test, also a primary analgesicscreening test, designed to measure the ability of a test agent toprevent phenyl-p-quinone-induced writhing in mice, described by Pearland Harris, J. Pharmacol. Exptl. Therap. 154, 319-323 (1966); the rattail flick radiant thermal heat analgesic (agonist) test described byD'Amour and Smith, J. Pharmacol. Exptl. Therap. 72, 74 (1941) asmodified by Bass and VanderBrook, J. Am. Pharm. Assoc. Sci. Ed. 41, 569(1956); and the phenazocine antagonist test, which is designed tomeasure the ability of a test agent to antagonize the effect ofphenazocine in the above-indicated rat tail flick response test,described by Harris and Pierson, J. Pharmacol. Exptl. Therap. 143, 141(1964).

The structures of the compounds of this invention were established bythe modes of synthesis, by elementary analyses and by ultraviolet,infrared and nuclear magnetic resonance spectra. The course of reactionsand homogeneity of the products were ascertained by thin layerchromatography.

The manner and process of making and using the invention, and the bestmode contemplated by the inventor of carrying out this invention, willnow be described so as to enable any person skilled in the art to whichit pertains to make and use the same. The melting points are uncorrectedunless noted otherwise.

In the various tables accompanying the following examples, the weightsof the principal, organic starting materials (S.M.) and products (Prod.)are given in grams in the appropriate columns headed "Wt.--", and themelting points of the final products, together with the solvent ofrecrystallization, are given in the last column.

Where weights of only one of several reactants are given, the weights ofsuch other reactants can be calculated on a proportionate molar basisfrom the amounts used in the example referred to for the preparativeprocedure employed. In some instances, the products were neithercharacterized nor purified, either by distillation or recrystallization,but rather were used directly in the next step as isolated from thereaction mixture.

The particular form of the starting material or product, whether base orsalt, is specified along with the weights by use of designations such as"base", "HCl", "HBr", etc. to indicate that the weights are given,respectively, for the free base or the hydrochloride, hydrobromide, etc.salts.

EXAMPLE 1

A. A solution of 11 g. (0.039 mole) of1-methyl-3-acetyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo-[g]quinolinehydrochloride in 20 ml. of a solution prepared by adding 89 ml. oftrimethylamine to 94 ml. of formic acid was stirred and heated underreflux for about 15 minutes. The mixture was allowed to cool, dilutedwith 100 ml. of water and washed with 50 ml. of diethyl ether. Theaqueous layer were basified with 15 ml. of concentrated ammoniumhydroxide and extracted twice with diethyl ether. The combined organicextracts, on washing once with water, drying and concentration todryness, afforded 10 g. of a solid residue which was dissolved in about30 ml. of absolute ethanol, the solution acidified with 13 ml. ofethereal hydrogen chloride, and diluted to 250 ml. with additionalether. The solid which separated was collected, washed, and set aside.The filtrate was washed with dilute ammonium hydroxide, dried, filteredand taken to dryness to give 3.1 g. of residue which was dissolved indiethyl ether and acidified with ethereal hydrogen chloride. The gummy,semi-crystalline material which separated was recrystallized fromethanol/ether to give 0.8 g. of6(eq)-ethyl-1,2,3,4,5,6,-hexahydro-3-methyl-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinehydrochloride, m.p. 192°-196° C.

B. An alternative method for the preparation of the compounds of formulaI from the compounds of formula II is illustrated by the followingprocedure:

A mixture of 10.0 g. (0.03 mole) of1-methyl-3-acetyl-5α-ethyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolinein 675 ml. of mesitylene and 25 ml. of formic acid was stirred andrefluxed for about eight hours while adding additional formic acid fromtime to time in order to maintain the pot temperature at 117°-119° C.The mixture was then cooled, extracted with dilute hydrochloric acid andthe acid extracts washed first with diethyl ether, then basified withammonium hydroxide and extracted once again with ethyl acetate. Theorganic extracts, on washing with brine, drying and evaporation todryness, afforded 8.4 g. of solid which was recrystallized from ethylacetate to give 3.7 g. of6(eq)-ethyl-1,2,3-4,5,6-hexahydro-3-methyl-8-hydroxy-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine,m.p. 190°-192° C.

Following a procedure similar to that described in Example 1A or Babove, using an appropriate 7-R₂ -1-R₁ -3-COR₅ -4aα-R₃ -5α-R₄-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline of formulaII, the following 8-R₂ -6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃-11(eq)-(oxo-lower-alkyl)-2,6-methano-3-benzazocines of formula I inTable 1a are prepared, where R₂ ', R₂ ", R₂ "' and R₈ in each case arehydrogen. The particular procedure used, that of Example 1A or 1B, isindicated by the letter designation (A) or (B), respectively, below theExample number. Unless noted otherwise, products were isolated as, andmelting points recorded for, the free base form.

                                      TABLE 1a                                    __________________________________________________________________________    Example                                                                            R.sub.1 /CH.sub.2 Z                                                                          R.sub.2                                                                           R.sub.3 /R.sub.4                                                                  Wt.II/Wt.I                                                                          m.p. (°C.)/Solv.                     __________________________________________________________________________    1C   CH.sub.3       H   CH.sub.3                                                                          10 (base)                                                                           207-208 (a)                                 (A)  CH.sub.2 CH.sub.2 COCH.sub.3                                                                     C.sub.2 H.sub.5                                                                   2.1 (salt)                                                                          ethanol/ether                                                           (a)                                               1D   C.sub.3 H.sub.5 --CH.sub.2 (c)                                                               H   H   16 (base)                                                                           206-208 (b)                                 (B)  CH.sub.2 CH.sub.2 COCH.sub.3                                                                     C.sub.2 H.sub.5                                                                   7.8 (base)                                                                          ethanol/ether                               1E   C.sub.6 H.sub.5 CH.sub.2                                                                     CH.sub.3 O                                                                        H   18.8 (base)                                                                         104-106                                     (B)  CH.sub.2 CH.sub.2 COCH.sub.3                                                                     CH.sub.3                                                                          7.2 (base)                                                                          ethanol                                     1F   C.sub.6 H.sub.5 CH.sub.2                                                                     CH.sub.3 O                                                                        H   39 (base)                                                                           122-125                                     (B)  CH.sub.2 CH.sub.2 COCH.sub.3                                                                     C.sub.2 H.sub.5                                                                   10.6 (base)                                                                         ethanol                                     1G   C.sub.6 H.sub.5 CH.sub.2                                                                     CH.sub.3 O                                                                        CH.sub.3                                                                          19.5 (base)                                                                         132-135                                     (B)  CH.sub.2 CH.sub.2 COCH.sub.3                                                                     CH.sub.3                                                                          11.5 (base)                                                                         ethanol                                     1H   CH.sub.3       CH.sub.3 O                                                                        H   4.9 (base)                                                                          132-134                                     (B)  CH.sub.2 CH.sub.2 COC.sub.5 H.sub. 11                                                            CH.sub.3                                                                          3.3 (salt)                                                                          ethanol/ether                                                           (d)                                               1J   C.sub.6 H.sub.5 CH.sub.2                                                                     H   CH.sub.3                                                                          55.3 (base)                                                                         229-232                                     (B)  CH.sub.2 CH.sub.2 COCH.sub.3                                                                     CH.sub.3                                                                          37.7 (HCl)                                                                          ethanol/ether                               1K   C.sub.6 H.sub.5 CH.sub.2                                                                     CH.sub.3 O                                                                        H   18.7 (base)                                                                         244-246                                     (B)  CH.sub.2 CH.sub.2 COC(CH.sub.3).sub.3                                                            CH.sub.3                                                                          15.3 (HCl)                                                                          ethanol/ether                               1L   C.sub.6 H.sub.5 CH.sub.2                                                                     CH.sub.3 O                                                                        CH.sub.3                                                                          39.2 (base)                                                                         248-255                                     (B)  CH.sub.2 CH.sub.2 COC(CH.sub.3).sub.3                                                            CH.sub.3                                                                          33.0 (HCl)                                                                          ethanol/ether                               1M   CH.sub.3       CH.sub.3 O                                                                        CH.sub.3                                                                          base  217-221                                     (B)  CH.sub.2 CH.sub.2 COCH.sub.2 CH.sub.3                                                            CH.sub.3                                                                          salt (e)                                                                            ethanol/ether                               1N   CH.sub.3       CH.sub.3 O                                                                        CH.sub.3                                                                          base  176-179                                     (B)  CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.2 CH.sub.3                                                    CH.sub.3                                                                          salt (e)                                                                            acetone/ether                               1P   C.sub.3 H.sub.5 --CH.sub.2 (c)                                                               CH.sub.3 O                                                                        CH.sub.3                                                                          base  219-220                                     (B)  CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.3 CH.sub.3                                                    CH.sub.3                                                                          HCl   acetone                                     1Q   CH.sub.3       CH.sub.3 O                                                                        H   base  183.5-185                                   (B)  CH.sub. 2 CH.sub.2 CO(CH.sub.2).sub.3 CH.sub.3                                                   CH.sub.3                                                                          salt (f)                                                                            acetone                                     1R   C.sub.6 H.sub.5 CH.sub.2                                                                     CH.sub.3 O                                                                        CH.sub.3                                                                          base  226-228                                     (B)  CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.3 CH.sub.3                                                    CH.sub.3                                                                          HCl   acetone                                     1S   CH.sub.3       CH.sub.3 O                                                                        CH.sub.3                                                                          base  146-148                                          CH.sub.2 CH.sub.2 COCH.sub.2 CH(CH.sub.3).sub.2                                                  CH.sub.3                                                                          salt (e)                                                                            acetone/ether                               1T   C.sub.6 H.sub.5 CH.sub.2                                                                     H   CH.sub.3                                                                          base  190-193                                          CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                                    CH.sub.3                                                                          HCl   acetone/ether                               1U   C.sub.6 H.sub.5 CH.sub.2                                                                     CH.sub.3 O                                                                        CH.sub.3                                                                          base  226-227                                          CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                                    CH.sub.3                                                                          HCl   acetone/ether                               1V   CH.sub.3       CH.sub.3 O                                                                        CH.sub.3                                                                          base  229-231                                          CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                      CH.sub.3                                                                          HCl acetone                                           1W   CH.sub.3       CH.sub.3 O                                                                        CH.sub.3                                                                          base  178-181 (g)                                      CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.5 CH.sub.3                                                    CH.sub.3                                                                          HCl   acetone/ether                               1X   CH.sub.3       CH.sub.3 O                                                                        H   base  oil                                              CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                          CH.sub.3                                                                          base                                              1Y   CH.sub.3       CH.sub.3 O                                                                        CH.sub.3                                                                          base  209-212                                          CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.3 CH.sub.3                                                    CH.sub.3                                                                          HCl   ethanol/ether                               1Z   CH.sub.3       CH.sub.3 O                                                                        CH.sub.3                                                                          base  137-141                                          CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.2 C.sub.6 H.sub.5                                             CH.sub.3                                                                          HBr . H.sub.2 O                                                                     H.sub.2 O                                   __________________________________________________________________________     (a) pToluenesulfonate hemihydrate                                             (b) Hydrochloride                                                             (c) Cyclopropylmethyl                                                         (d) pToluenesulfonate                                                         (e) Methanesulfonate                                                          (f) Picrate                                                                   (g) The ptoluenesulfonate has m.p. 188-190° C. (from acetone)     

Following a procedure similar to that described in Example 1A or 1Babove, using an appropriate 7-R₂ -1-R₁ -3-lower-alkanoyl-4aα-R₃ -5α-R₄-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline of formulaII, there are obtained the following 8-R₂ -6(eq)-R₄-1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-(CH₂ CH₂COR₅)-2,6-methano-3-benzazocines of formula I in Table 1b, where in eachcase R₂ ', R₂ ", R₂ "' and R₈ are each hydrogen.

                  TABLE 1b                                                        ______________________________________                                        Example R.sub.1 /CH.sub.2 Z R.sub.2  R.sub.3 /R.sub.4                         ______________________________________                                        1AA     CH.sub.3            CH.sub.3 O                                                                             CH.sub.3                                         CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                                              C.sub.2 H.sub.5                          1AB     C.sub.6 H.sub.5 CH.sub.2                                                                          CH.sub.3 O                                                                             CH.sub.3                                         CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                    CH.sub.3                                 1AC     CH.sub.3            CH.sub.3 O                                                                             CH.sub.3                                         CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                    C.sub.2 H.sub.5                          1AD     CH.sub.3            CH.sub.3 O                                                                             CH.sub.3                                         CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.3 CH(CH.sub.3).sub.2                                                    CH.sub.3                                 ______________________________________                                    

Following a procedure similar to that described above in Example 1A or1B, using an appropriate 7-R₂ -8-R₂ '-1-R₁ -3-lower-alkanoyl-4aα-R₃-5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline offormula II, it is contemplated that the following 8-R₂ -9-R₂ '-6(eq)-R₄-1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-(CH₂ CH₂COR₅)-2,6-methano-3-benzazocines of formula I in Table 1c can beprepared, where in each case R₂ ", R₂ "' and R₈ are hydrogen.

                                      TABLE 1c                                    __________________________________________________________________________    Example                                                                            R.sub.1 /CH.sub.2 Z                                                                         R.sub.2 /R.sub.2 '                                                                     R.sub.3 /R.sub.4                                  __________________________________________________________________________    1AE  C.sub.6 H.sub.5 CH.sub.2                                                                    H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        C.sub.2 H.sub.5                                   1AF  CH.sub.3      H        CH.sub.3                                               CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1AG  C.sub.6 H.sub.5 CH.sub.2                                                                    H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1AH  C.sub.6 H.sub.5 CH.sub.2                                                                    HO       H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1AJ  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COC.sub.3 H.sub.7                                                         H        C.sub.2 H.sub.5                                   1AK  cyclohexyl    CH.sub.3 S                                                                             H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1AL  4-BrC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                       CH.sub.3 O                                                                             H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1AM  4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                       CH.sub.3 CONH                                                                          H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1AN  4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                        C.sub.2 H.sub.5 OCONH                                                                  H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1AP  4-Cl-3-CH.sub.3 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                           H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1AQ  3-CH.sub.3 COOC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                             H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1AR  3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                    H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1AS  4-CH.sub.3 SC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                               H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1AT  3-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1AU  3-CH.sub.3 CONHC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                            H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                           1AV                                                                                ##STR41##     H        H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1AW  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                Cl       CH.sub.3                                          1AX  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                Br       CH.sub.3                                          1AY  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                F        CH.sub.3                                          1AZ  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                CF.sub.3 CH.sub.3                                          1BA  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                CH.sub.3 CH.sub.3                                          1BB  CH.sub.3      C.sub.6 H.sub.5                                                                        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.3                                          1BC  CH.sub.3 CH.sub.2 CH.sub.2 COCH.sub.3                                                        ##STR42##                                                                             H CH.sub.3                                        1BD  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        H                                                 1BE  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.2 CH.sub.2 Cl                               1BF  CH.sub.3 CH.sub.2 CH.sub.2 COCH.sub.3                                                       H H                                                                                    ##STR43##                                         1BG  CH.sub.3 CH.sub.2 CH.sub.2 COCH.sub.3                                                       H H                                                                                    ##STR44##                                        1BH  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.2 CH.sub.2 OCH.sub.3                       1BJ  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COC.sub.6 H.sub.5                                                         H        C.sub.2 H.sub.5                                   1BK  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.2 CH.sub.2 SC.sub.6 H.sub.5                1BL  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.2 CH.sub.2 SOC.sub.6 H.sub.5               1BM  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CHCH.sub.2                                        1BN  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.2 CH.sub.2 SCH.sub.3                       1BP  CH.sub.3      H        H                                                      CH.sub.2 CH.sub.2 COCH.sub.3                                                                H        CH.sub.2 CH.sub.2 OH                              1BQ  CH.sub.3      CH.sub.3 O                                                                             CH.sub.3                                               COCH.sub.2cyclopropyl                                                                       H        CH.sub.3                                          1BR  CH.sub.3      CH.sub.3 O                                                                             CH.sub.3                                               COCH.sub.2cyclopentyl                                                                       H        CH.sub.3                                          1BS  CH.sub.3      CH.sub.3 O                                                                             CH.sub.3                                               COCH.sub. 2cyclohexyl                                                                       H        CH.sub.3                                          1BT  CH.sub.3      CH.sub.3 O                                                                             CH.sub.3                                               CO(CH.sub.2).sub.2cyclohexyl                                                                H        CH.sub.3                                          __________________________________________________________________________

EXAMPLE 1BU

Heating1,5α,8-trimethyl-3-acetyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolinewith formic acid in mesitylene using the procedure described above inExample 1B affords3,6(eq),9-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine.

EXAMPLE 1BV

Heating1-benzyl-3-acetyl-3,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolinewith formic acid in mesitylene using the procedure described above inExample 1B affords3-benzyl-11(ax),6(eq)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(2-methyl-3-oxobutyl)-2,6-methano-3-benzazocine.

EXAMPLE 1BW

Heating1-acetyl-3-pentanoyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolinewith formic acid in mesitylene using the procedure described above inExample 1B affords3-acetyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxoheptyl)-2,6-methano-3-benzazocine.

EXAMPLE 2

A. A solution of 27.0 g. (0.072 mole) of3-benzyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine(described in Example 1E) was dissolved in 250 ml. of 48% hydrobromicacid and the mixture heated under reflux for about eleven hours. Themixture was concentrated to a small volume in vacuo, diluted with 100ml. of water, concentrated again, and finally boiled with about 50 ml.of isopropanol. The solid which separated was collected and dried togive 23 g. of3-benzyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinehydrobromide, m.p. 156°-165° C.

Following a procedure similar to that described in Example 2A aboveusing an appropriate 8-methoxy-3-methyl-11(ax)-R₃-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-CH₂ CH₂ COR₅-2,6-methano-3-benzazocine of formula I, the following 8-hydroxy-3-R₁-11(ax)-R₃ -6(eq)-R₄ -1,2,3,4,5,6-hexahydro-11(eq)-CH₂ CH₂ COR₅-2,6-methano-3-benzazocines of formula I in Table 2a were preparedwhere, unless noted otherwise, in each case R₂ is hydroxy, R₂ ', R₂ ",R₂ '" and R₈ are each hydrogen, and R₁, R₃ and R₄ are each methyl. Theform (base or salt) of the starting material and product is given inparentheses along with the respective weights.

                  TABLE 2a                                                        ______________________________________                                        Ex-                                                                           am-                                                                           ple  R.sub.5       Wt.S.M./Wt.Prod.                                                                            m.p. (°C.)/Solv.                      ______________________________________                                         2B  C.sub.5 H.sub.11 (b)                                                                        4.0 (salt) (a)                                                                              107-109                                                         1.8 (base)    ethanol                                      2C   C.sub.2 H.sub.5                                                                             3.5 (base)    265-268                                                         2.5 (HCl)     ethanol/ether                                2D   C.sub.3 H.sub.7                                                                             5.0 (base)    264-266                                                         3.7 (HCl)     ethanol                                      2E   C.sub.4 H.sub.9 (b)                                                                         5.1 (base)    120-122                                                         1.9 (base)    ethyl acetate                                2F   (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                         4.0 (HCl)     260-263 (c) (d)                                                 3.3 (HCl)     isopropanol                                  2G   C.sub.6 H.sub.13                                                                            4.5 (HCl)     206-209                                                         2.8 (HCl)     isopropanol                                  2H   C.sub.5 H.sub.11                                                                            4.5 (HCl)     252-255 (e)                                                     1.7 (HCl)     isopropanol                                  2J   CH.sub.2 CH(CH.sub.3).sub.2                                                                 5.5 (base)    251-254                                                         2.6 (HCl)     ethanol                                      2K   (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                         7.0 (base)    101-103.5                                         (b)           1.6 (base)    ethyl acetate/                                                                hexane                                       2L   (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                            8.1 (salt) (a)                                                                              233-235 (s)                                                     1.6 (CH.sub.3 SO.sub.3 H)                                                                   ethanol                                      2M   . CH.sub.3    5.8 (base)    170-173 (f)                                                     1.3 (base)    ethanol                                      2N   (CH.sub.2).sub.4 CH.sub.3 (g)                                                               3.3 (base)    140-143                                                         1.4 (base)    ethanol                                      2P   (CH.sub.2).sub.4 CH.sub.3 (h)                                                               9.7 (base)    138.5-141.5                                                     4.4 (base)    ethanol                                      2Q   (CH.sub.2).sub.4 CH.sub.3 (i)                                                               9.2 (base)    253-257                                                         8.6 (HCl)     acetone/ether                                2R   (CH.sub.2).sub.3 CH(CH.sub.3).sub.2                                                         6.5 (base)    116.5-118.5                                                     4.2 (base)    ethyl acetate/                                                                hexane                                       2S   (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                         5.4 (base)    264.5-267                                         (g)           2.2 (HCl)     ethanol                                      2T   (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                         21.7 (base)   160.5-163.5                                       (i)           24.0 (HCl)    ethanol/ether                                2U   (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                         4.0 (HCl)     270-273                                           (j)           3.0 (HCl)     ethanol/ether                                2V   (CH.sub.2).sub.2 cyclopentyl                                                                12.7 (base)   230-235 (k)                                                     4.8 (H.sub.2 SO.sub.4)                                                                      ethanol/ether                                2W   C.sub.6 H.sub.5                                                                             5.8 (base)    182-184.5                                                       1.9 (base)    ethyl acetate/                                                                hexane                                       2X   3--CH.sub.3 C.sub.6 H.sub.4                                                                 6.5 (base)    203-206                                                         1.9 (base)    methanol                                     2Y   4--CH.sub.3 C.sub.6 H.sub.4                                                                 3.0 (base)    273-276                                                         1.8 (CH.sub.3 SO.sub.3 H)                                                                   methanol                                     2Z   CH.sub.2 C.sub.6 H.sub.5                                                                    4.2 (base)    228-231                                                         3.1 (CH.sub.3 SO.sub.3 H)                                                                   methanol                                     2AA  CH.sub.2 C.sub.6 H.sub.4 CH.sub.3 (3)                                                       5 (base)      232- 234                                                        3.0 (CH.sub.3 SO.sub.3 H)                                                                   methanol                                     2AB  CH(CH.sub.3).sub.2                                                                          5.3 (base)    263-266                                                         1.9 (HCl)     isopropanol/                                                                  ether                                        2AC  cyclopentyl   6.8 (base)    142-148                                                         1.8 (base)    ethyl acetate/                                                                hexane                                       2AD  (CH.sub.2).sub.2 cyclobutyl                                                                 5.5 (CH.sub.3 SO.sub.3 H)                                                                   271-275                                                         3.9 (HCl)     methanol/                                                                     ether                                        2AE  CH.sub.2 cyclobutyl                                                                         2.4 (base)    278-281                                                         1.6 (HCl)     isopropanol/                                                                  methanol                                     2AF  (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                         5.0 (base)    218-223                                           (l)           2.6 (CH.sub.3 SO.sub.3 H)                                                                   ethanol/ether                                2AG  (CH.sub.2).sub.4 CH.sub.3 (l)                                                               3.9 (base)    192-195                                                         2.4 (CH.sub.3 SO.sub.3 H)                                                                   ethanol/ether                                2AH  (CH.sub.2).sub.4 CH.sub.3 (m)                                                               6.5 (base)    213-217                                                         5.7 (H.sub.2 SO.sub.4)                                                                      ethanol                                      2AJ  (CH.sub.2).sub.4 CH.sub.3 (n)                                                               5.0 (base)    207-211                                                         2.7 (H.sub.2 SO.sub.4)                                                                      ethanol/ether                                2AK  C(CH.sub.3).sub.2 (CH.sub.2).sub.3 CH.sub.3                                                 3.1 (base)    178-181                                                         1.4 (CH.sub.3 SO.sub.3 H)                                                                   methanol/                                                                     acetone                                      2AL  C(CH.sub.3).sub.2 C.sub.2 H.sub.5                                                           6.7 (base)    253-255                                                         4.1 (CH.sub.3 SO.sub.3 H)                                                                   methanol/                                                                     ether                                        2AM  C(CH.sub.3).sub.3 (CH.sub.2).sub.2 CH.sub.3                                                 ca. 7.6 (CH.sub.3 SO.sub.3 H)                                                               217-220                                                         1.3 (CH.sub.3 SO.sub.3 H)                                                                   methanol                                     2AN  (CH.sub.2).sub.4 CH.sub.3 (p)                                                               21.4 (base)   196-199                                                         20.0 (HBr)    (q)                                          2AP  CH.sub.2 cyclopentyl                                                                        8.9 (base)    192-196                                                         6.4 (H.sub.2 SO.sub.4)                                                                      ethanol/ether                                2AQ  (CH.sub.2).sub.2 CH(CH.sub.3).sub.3                                                         12.7 (base)   185-190                                                         10.4 (HBr)    (r)                                          ______________________________________                                         (a) pToluenesulfonate-                                                        (b) R.sub.3 is hydrogen                                                       (c) A sample of the racemic base was resolved with l and dmandelic acid t     give, respectively, the lmandelate, m.p. 190-193° C. (from             acetone), [α].sub.D.sup.25 = -6.9°, and the dmandelate, m.p.     191-193° C. (from acetone), [α].sub.D.sup.25 = +5.5°.     Cleavage of the two mandelate salts to the respective free bases and          conversion of the latter to the hydrochlorides gave, respectively, the l      and dhydrochlorides, m.p. 240-242° C. (from ethanol/ether),            [α].sub.D.sup.25 = -32.2° and m.p. 240-242° C. (from      ethanol/ether), [α].sub.D.sup.25 = +32.1°. The l and             dmethanesulfonates showed, respectively, m.p. 215-218° C.,             [α].sub.D.sup.25 = -26.3° and m.p. 214-216° C.,           [α].sub.D.sup.25 = +27.3°. The dhydrobromide showed m.p.         237-239° C., [α].sub.D.sup.22 = + 28.9°.                  (d) The methanesulfonate has m.p. 189-191° C. (from acetone/diethy     ether).                                                                       (e) The methanesulfonate has m.p. 178-179° C. (from acetone); the      free base has m.p. 131-133° C. (from methanol); and the                2naphthalenesulfonate has m.p. 195-198° C. (from methanol/diethyl      ether). A sample of the racemic base was resolved with l and d mandelic       acid to give, respectively, the l mandelate, m.p. 196-198° C. (fro     acetone), [α].sub.D.sup.25 = -5.2°, and the d mandelate, m.p     195-197° C. (from acetone), [α].sub.D.sup.25 = +5.3°.     Cleavage of the two mandelate salts to the respective free bases and          conversion of the latter to the methanesulfonates gave, respectively, the     l and d methanesulfonates, m.p. 212-214° C. (from methanol/diethyl     ether), [α].sub.D.sup.25 = -25.7° and m.p. 212-214° C     (from methanol/diethyl ether), [α].sub.D.sup.25 = +26.7°.        (f) The methanesulfonate has m.p. 265-268° C. (from ethanol/ether)     (g) R.sub.4 is C.sub.2 H.sub.5                                                (h) R.sub.1 is hydrogen                                                       (i) R.sub.1 is benzyl                                                         (j) R.sub.3 /R.sub.4 are --(CH.sub.2).sub.4                                    (k) A sample of the racemic base was resolved with d and l mandelic acid     to give, respectively, the dmandelate m.p. 200-202° C. (from           acetone) and the lmandelate, m.p. 198-201° C. (from acetone).          Cleavage of the mandelate salts to the respective free bases and              conversion of the latter to the methanesulfonates gave, respectively, the     l and d methanesulfonates, m.p. 246-249° C. (from methanol/ether),     [α].sub.D.sup.25 = -24.4° and m.p. 246-248° C. (from      methanol/ether), [α].sub.D.sup.25 = +25.8°.                      (l) R.sub.3 and R.sub.4 are both C.sub.2 H.sub.5.                             (m) R.sub.3 and R.sub.4 together are --(CH.sub.2).sub.4 --.                   (n) R.sub.3 is C.sub.2 H.sub.5 ; R.sub.4 is CH.sub.3.                         (p) R.sub.1 is benzyl.                                                        (q) The crude hydrobromide salt as isolated directly from the reaction        mixture showed m.p. 196-199° C. A small sample recrystallized from     ethanol/ether gave m.p. 201-205° C.                                    (r) The crude hydrobromide salt as isolated directly from the reaction        mixture showed m.p. 185-190° C. A small sample recrystallized from     ethanol/ether gave m.p. 199-202°  C.                                   (s) The ethanesulfonate shows m.p. 226-228° C. (from acetone).    

Following a procedure similar to that described in Example 2 above,using an appropriate8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-CH₂ CH₂COR₅ -2,6-methano-3-benzazocine of formula I, the following8-hydroxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-CH₂ CH₂COR₅ -2,6-methano-3-benzazocines are prepared where, in each case, R₂ ishydroxy; R₂ ', R₂ ", R₂ "' and R₈ are each hydrogen; and R₁, R₃ and R₄are each methyl.

                  TABLE 2b                                                        ______________________________________                                        Example          R.sub.5                                                      ______________________________________                                        2AR              CH.sub.2 --cyclopropyl                                       2AS              CH.sub.2 --cyclopentyl                                       2AT              CH.sub.2 --cyclohexyl                                        2AU              CH.sub.2 CH.sub.2 --cyclohexyl                               ______________________________________                                    

EXAMPLE 3

A. A solution of 23.1 g. (0.05 mole) of3-benzyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinehydrobromide (described in Example 2A) in 150 ml. of DMF was reducedwith hydrogen over 10 g. of 10% palladium-on-charcoal using theprocedure described in Example 9A below. The product obtained wasrecrystallized from ethanol to give 16.1 g. of8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinehydrobromide, m.p. 235°-237° C. (from ethanol).

Following a procedure similar to that described in Example 3A aboveusing an appropriate 8-R₂ -3-benzyl-11(ax)-R₃ -6(eq)-R₄-1,2,3,4,5,6-hexahydro-11(eq)-CH₂ Z-2,6-methano-3-benzazocine of formulaI, the following 8-R₂ -11(ax)-R₃ -6(eq)-R₄-1,2,3,4,5,6-hexahydro-11(eq)-CH₂ Z-2,6-methano-3-benzazocines offormula I in Table 3 were prepared where in each case R₁, R₂ ', R₂ ", R₂"' and R₈ are hydrogen. Compounds for which no value for R₆ is given arethe ketones (Z is CH₂ COR₅). Otherwise the compounds are the carbinols[Z is CH₂ C(R₅)(R₆)OH]. The form (base or salt) of the starting materialand product is given in parentheses along with the respective weights.

                                      TABLE 3                                     __________________________________________________________________________    Example                                                                            R.sub.2                                                                           R.sub.5 /R.sub.6                                                                       R.sub.3 /R.sub.4                                                                  Wt.S.M./Wt.Prod.                                                                        m.p. (°C.)/Solv.                       __________________________________________________________________________    3B   CH.sub.3 O                                                                        CH.sub.3 H   21.2 (base)                                                                             189-193                                                --       CH.sub.3                                                                          11.4 (HCl)                                                                              ethanol                                       3C   CH.sub.3 O                                                                        C.sub.5 H.sub.11                                                                       CH.sub.3                                                                          13.8 (HCl)                                                                              179-182                                                --       CH.sub.3                                                                          5,8 (HCl) methanol/ether                                3D   H   C.sub.5 H.sub.11                                                                       CH.sub.3                                                                          4.2 (HCl) 155-157                                                --       CH.sub.3                                                                          2.2 (HCl) acetone/ether                                 3E   CH.sub.3 O                                                                        CH.sub.3 CH.sub.3                                                                          11.8 (HCl)                                                                              130.0-132.5                                            CH.sub.3 CH.sub.3                                                                          6.5 (base)                                                                              --                                            3F   CH.sub.3 O                                                                        C.sub.4 H.sub.9                                                                        CH.sub.3                                                                          9.0 (HCl) 170-172                                                --       CH.sub.3                                                                          6.3 (HCl) acetone                                       3G   HO  (CH.sub.2).sub.4 CH.sub.3                                                              CH.sub.3                                                                          4.7 (HCl) 209-211                                                --       CH.sub.3                                                                          2.6 (HCl) (a)                                                                           ethanol                                       3H   HO  (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                    CH.sub.3                                                                          24.0 (HCl)                                                                              160.5-163.5                                            --       CH.sub.3                                                                          4.6 (base)                                                                              ethyl acetate                                 3J   CH.sub.3 O                                                                        (CH.sub.2 ).sub.2 CH(CH.sub.3).sub.2                                                   CH.sub.3                                                                          17.5 (HCl)                                                                              158-167                                                         CH.sub.3                                                                          2.8 (H.sub.3 PO.sub.4)                                                                  water                                         __________________________________________________________________________     (a) The free base has m.p. 137-141° C. (from ethyl acetate)       

EXAMPLE 4

A. A mixture of 11.4 g. (0.03 mole) of8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinehydrobromide (described in Example 3A), 5.4 g. of sodium bicarbonate and5.2 g. (0.04 mole) of cyclopropylmethyl bromide in 150 ml. of DMF washeated under reflux for about nine hours and then concentrated to asmall volume in vacuo. The residue was partitioned between ammoniumhydroxide and ethyl acetate, the organic layer separated, and theaqueous layer extracted with additional portions of ethyl acetate. Thecombined extracts were washed once with water, then with brine, dried,filtered and taken to dryness to give 12.1 g. of crude product which wasconverted to the hydrochloride salt. The latter was recrystallized oncefrom acetonitrile and once from ethanol/ether to give 5.2 g. of3-cyclopropylmethyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinehydrochloride, m.p. 147°-154° C.

B. Following a procedure similar to that described in Example 4A,3-cyclopropylmethyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine(12.9 g.) was prepared by reaction of 15.0 g. (0.04 mole) of8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine(described in Example 3B) with cyclopropylmethyl bromide in the presenceof sodium bicarbonate in DMF.

C.3,6(eq)-Dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinep-toluenesulfonate (9.9 g.) m.p. 199°-201° C. (from ethanol), wasprepared by reductive alkylation of 11.4 g. of8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinehydrobromide (described in Example 3A) with formaldehyde andtriethylamine over palladium-on-charcoal in ethanol under about 50p.s.i. of hydrogen, the product being isolated in the manner describedabove in Example 4A.

D.3,6-(eq)-Dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine(7.5 g.) was prepared by reductive alkylation of 8.2 g. of8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinehydrochloride (described in Example 3B) with formaldehyde andtriethylamine over palladium-on-charcoal in ethanol under about 50p.s.i. of hydrogen using the procedure described in Example 4C. Thehydrochloride salt gives m.p. 181°-183° C. (from ethanol).

E.3,6(eq),11(ax)-Trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinehydrochloride (5.5 g.), m.p. 212°-214° C. (from acetone) was prepared byreductive alkylation of 7.2 g. of6(eq),11(ax)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinewith 2.0 cc. of 37% aqueous formaldehyde and 3.8 cc. of 97% formic acid.The p-toluenesulfonate gives m.p. 200°-201° C. (from ethanol/diethylether).

F.3-Cyclobutylmethyl-6(eq),11(ax)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinehydrochloride (2.1 g.), m.p. 207°-209° C. (from acetone) was prepared byreaction of 0.15 mole (from 5.9 g. of the hydrochloride) of6(eq),11(ax)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinewith 2.5 g. of cyclobutylmethyl bromide in 60 ml. of DMF in the presenceof 1.5 g. of sodium bicarbonate.

G.3,6(eq),11(ax)-Trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxoheptyl)-2,6-methano-3-benzazocinehydrochloride (3.2 g.), m.p. 209°-211° C. (from acetone/ether) wasprepared by the reductive alkylation of 5.3 g. of6(eq),11(ax)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxoheptyl)-2,6-methano-3-benzazocinewith 1.5 ml. of 37% aqueous formaldehyde in 100 ml. of ethanol over 1.0g. of palladium-on charcoal under a hydrogen pressure of about 45 p.s.i.

H.3-Ethyl-6(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinewas prepared by reaction of 0.02 mole of6(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinewith 5 ml. of acetic anhydride in 50 ml. of dry pyridine. The resulting3-acetyl-6(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocine(3.4 g., m.p. 56°-59° C.) was dissolved in 100 ml. of toluene with 11ml. of ethylene glycol and 0.5 g. of p-toluenesulfonic acid and themixture distilled until no further water was produced. The correspondingethylene glycol ketal (4.0 g.) was isolated as an oil from the toluenesolution after washing the latter with aqueous bicarbonate. Reduction ofthe ketal with 1.2 g. of lithium aluminum hydride in 150 ml. oftetrahydrofuran using the procedure described above in Example 8Aafforded 1.7 g. of the final product in the form of the ethylene glycolketal hydrochloride, m.p. 198°-201° C. (from ethyl acetate). Hydrolysisof the latter in dilute hydrochloric acid gives the free ketone.

J.3-Cyclopropylmethyl-6(eq),11(ax)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinemethanesulfonate (2.4 g.), m.p. 211°-213° C. (from methanol) wasprepared by reaction of 3.8 g. (0.01 mole) of6(eq),11(ax)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinewith 1.7 g. (0.013 mole) of cyclopropylmethyl bromide in 25 ml. of DMFin the presence of 2.1 g. of sodium bicarbonate.

K.3-Ethyl-6(eq),11(ax)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-6-methylheptyl)-2,6-methano-3-benzazocine(1.6 g.) m.p. 116°-118.5° C. (from ethyl acetate/hexane) was prepared byreaction of 6.0 g. (0.018 mole) of6(eq),11(ax)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-6-methylheptyl)-2,6-methano-3-benzazocinewith 2.11 ml. (0.026 mole) of ethyl iodide in 45 ml. of DMF in thepresence of 2.2 g. of sodium bicarbonate.

L.3-Cyclopropylmethyl-6(eq),11(ax)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-6-methylheptyl)-2,6-methano-3-benzazocinemethanesulfonate (2.2 g.), m.p. 190.5-193.0 (from ethanol/ether) wasprepared by reaction of 4.2 g. (0.012 mole) of6(eq),11(ax)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-6-methylheptyl)-2,6-methano-3-benzazocinewith 1.8 g. (0.013 mole) of cyclopropylmethyl bromide in 30 ml. of DMFin the presence of 1.1 g. of sodium bicarbonate.

M.3-Ethyl-6(eq),11(ax)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocine(3.8 g.), m.p. 140.5°-144° C. (from ethanol) was prepared by reaction of6.2 g. (0.018 mole) of6(eq),11(ax)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinewith 2.2 ml. (0.027 mole) of ethyl iodide in 45 ml. of DMF in thepresence of 2.3 g. of sodium bicarbonate.

N.3-Propyl-6(eq),11(ax)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinemethanesulfonate (2.1 g.), m.p. 154°-157° C. (from ethanol) was preparedby reaction of 3.6 g. (0.011 mole) of6(eq),11(ax)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinewith 1.53 ml. (0.016 mole) of propyl iodide in 30 ml. of DMF in thepresence of 1.32 g. of sodium bicarbonate.

P.3-(2-Phenylethyl)-6(eq),11(ax)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-6-methylheptyl)-2,6-methano-3-benzazocinehydrosulfate (1.9 g.), m.p. 206°-208° C. (from ethanol/ether) wasprepared by reaction of 5.0 g. (0.014 mole) of6(eq),11(ax)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-6-methylheptyl)-2,6-methano-3-benzazocinewith 2.1 ml. (0.015 mole) of 2-phenylethyl bromide in 70 ml. of DMF inthe presence of 1.3 g. of sodium bicarbonate.

Following a procedure similar to that described in Example 4A, using the8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinedescribed in Example 3A and an appropriate alkylating agent, R₁ Hal,there are prepared the following compounds of formula I in Table 4,where in each instance R₂ is HO; R₂ ', R₂ ", R₂ "' and R₃ are eachhydrogen; R₄ is CH₃ ; and CH₂ Z is CH₂ CH₂ COCH₃.

                  TABLE 4                                                         ______________________________________                                        Example           R.sub.1                                                     ______________________________________                                        4Q                CH.sub.2 CH═CH.sub.2                                    4R                CH.sub.2 CH═C(CH.sub.3).sub.2                           4S                CH.sub.2 C.tbd.CH                                           4T                CH.sub.2 C.tbd.CCH.sub.3                                    4U                CH.sub.2 CH═CCl.sub.2                                   ______________________________________                                    

EXAMPLE 5

A. A solution of 4.7 g. (0.16 mole) of6(eq)-ethyl-1,2,3,4,5,6-hexahydro-3-methyl-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine(from the hydrochloride described in Example 1 A) in 28 ml. of diethylether was added dropwise with stirring to 28 ml. (0.05 mole) of a 1.8 Msolution of methyl lithium in diethyl ether. The mixture was stirredunder nitrogen for about one hour, poured into an ice/aqueous ammoniumchloride solution, and the ether layer separated and washed with water.The organic layer was dried, filtered, and taken to dryness to give 4.9g. of residue which was converted to the methanesulfonate salt inmethanol/diethyl ether. The latter was recrystallized frommethanol/diethyl ether to give 2.5 g. of3-methyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocinemethanesulfonate, m.p. 173°-174° C.

Following a procedure similar to that described in Example 5A, using anappropriate 8-R₂ -6-(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine described above and anappropriate lower-alkyl lithium (R₆ Li), there were prepared the 8-R₂-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁-11(eq)-(3-methyl-3-hydroxy-lower-alkyl)-2,6-methano-3-benzazocines offormula I in Table 5a where, in each instance, R₂ ', R₂ ", R₂ "' and R₇are hydrogen. Unless noted otherwise, products were isolated as, andmelting points recorded for, the free base form.

                                      TABLE 5a                                    __________________________________________________________________________    Example                                                                            R.sub.1 /R.sub.2                                                                      R.sub.3 /R.sub.4                                                                  R.sub.5 /R.sub.6                                                                       Wt.S.M./Wt.Prod.                                                                        m.p.(°C./Solv.                     __________________________________________________________________________    5 B  CH.sub.3                                                                              H   CH.sub.3 3.6 (base)                                                                              203-206                                        HO      C.sub.2 H.sub.5                                                                   CH.sub.3 1.2 (base)                                                                              ethyl acetate                             5 C  C.sub.3 H.sub.5 --CH.sub.2 (a)                                                        H   CH.sub.3 4.0 (base)                                                                              184-186                                        H       C.sub.2 H.sub.5                                                                   CH.sub.3 2.2 (HCl) CH.sub.3 CN/ether                         5 D  C.sub.3 H.sub.5 --CH.sub.2 (a)                                                        H   CH.sub.3 11.4 (base)                                                                             138-140                                        HO      CH.sub.3                                                                          CH.sub.3 3.3 (base)                                                                              ethyl acetate                             5 E  C.sub.6 H.sub.5 CH.sub.2                                                              H   CH.sub.3 3.78 (base)                                                                             252                                            CH.sub.3 O                                                                            CH.sub.3                                                                          t-C.sub. 4 H.sub.9                                                                     1.25 (HCl)                                                                              ethanol                                   5 F  CH.sub.3                                                                              H   CH.sub.3 4.2 (base)                                                                              182-183                                        HO      CH.sub.3                                                                          CH.sub.3 2.6 (base)                                                                              ethyl acetate                             5 G  CH.sub.3                                                                              H   CH.sub.3 7.5 (base)                                                                              oil                                            CH.sub.3 O                                                                            CH.sub.3                                                                          C.sub.4 H.sub.9                                                                        11.3 (base)                                         5 H  C.sub.6 H.sub.5 CH.sub.2                                                              H   CH.sub.3 3.78 (base)                                                                             oil                                            CH.sub. 3 O                                                                           CH.sub.3                                                                          C.sub.2 H.sub.5                                                                        4.5 (base)                                          5 J  C.sub.3 H.sub.5 --CH.sub.2 (a)                                                        H   CH.sub.3 13.4 (base)                                                                             184-185 (c)                                    HO (c)  CH.sub.3                                                                          C.sub.4 H.sub.9                                                                        10.2 (b)  ethanol/ether                             5 K  C.sub.6 H.sub.5 CH.sub.2                                                              H   CH.sub.3 20.0 (base)                                                                             oil                                            CH.sub.3 O                                                                            CH.sub.3                                                                          C.sub.3 H.sub.7                                                                        21.8 (base)                                         5 L  C.sub.6 H.sub.5 CH.sub.2                                                              CH.sub.3                                                                          CH.sub.3 11.5 (base)                                                                             223-227                                        CH.sub.3 O                                                                            CH.sub.3                                                                          t-C.sub. 4 H.sub.9                                                                     2.4 (HCl) ethanol/ether                             5 M  C.sub.3 H.sub.5 CH.sub.2 (a)                                                          H   CH.sub.3 12.0 (base)                                                                             --                                             CH.sub.3 O                                                                            C.sub.2 H.sub.5                                                                   t-C.sub.4 H.sub.9                                                                      12.9 (base)                                                                             --                                        5 N  C.sub.6 H.sub.5 CH.sub.2                                                              CH.sub.3                                                                          CH.sub.3 18.8 (HCl)                                                                              246-248                                        H       CH.sub.3                                                                          t-C.sub.4 H.sub.9                                                                      3.6 (HCl) ethanol/ether                             5 P  C.sub.6 H.sub.5 CH.sub.2                                                              CH.sub.3                                                                          CH.sub.3 13.7 (base)                                                                             233-234                                        CH.sub.3 O                                                                            CH.sub.3                                                                          CH.sub.3 12.1 (HCl)                                                                              ethanol/ether                             5 Q  C.sub.6 H.sub.5 CH.sub.2                                                              H   t-C.sub.4 H.sub.9                                                                      37.7 (base)                                                                             249                                            CH.sub. 3 O                                                                           CH.sub.3                                                                          CH.sub.3 8.7 (base)                                                                              ethanol/ether                             5 R  C.sub.6 H.sub.5 CH.sub.2                                                              CH.sub.3                                                                          t-C.sub.4 H.sub. 9                                                                     11.9 (base)                                                                             249-252                                        CH.sub.3 O                                                                            CH.sub.3                                                                          CH.sub.3 4.0 (HCl) ethanol                                   5 S  CH.sub.3                                                                              CH.sub.3                                                                          (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                    20.4 (base)                                              CH.sub.3 O                                                                            CH.sub.3                                                                          CH.sub.3 (d)                                                 __________________________________________________________________________     (a) Cyclopropylmethyl                                                         (b) Methanesulfonate                                                          (c) Starting material was methyl ether described in Example 4B, and the       product obtained from reaction with butyl lithium was cleaved, without        characterization, to the 8HO compound with sodium propanethiol using the      procedure described in Example 9A.                                            (d) The product was separated into two isomeric pairs of racemates by hig     pressure liquid chromatography on silica gel in 60% hexane/40% ethyl          acetate. There was thus obtained 3.6 g. of one isomer, designated Isomer      I, isolated as the hydrochloride, m.p. 195-197° C. (from               ethanol/ether) and 3.5 g. of another isomer, designated Isomer II,            isolated as the free base, as a syrup.                                   

Following a procedure similar to that described in Example 5A, using anappropriate 8-R₂ -6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃-11(eq)-CH₂ CH₂ COR₅ -2,6-methano-3-benzazocine described above and anappropriate lower-alkyl, phenyl or phenyl-lower-alkyl lithium, R₆ Li,there are obtained the respective 8-R₂ -6(eq)-R₄-1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂ CH₂C(R₅)(R₆)OH-2,6-methano-3-benzazocines of formula I listed in Table 5bwhere, in each instance, R₂ ', R₂ ", R₂ "', R₇ and R₈ are hydrogen.

                                      TABLE 5b                                    __________________________________________________________________________    Example                                                                            R.sub.1      R.sub.2 R.sub.3                                                                          R.sub.4                                                                          R.sub.5                                                                          R.sub.6                                    __________________________________________________________________________    5 T  cyclohexyl   CH.sub.3 S                                                                            H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                   5 U  4-BrC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                      CH.sub.3 O                                                                            H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                   5 V  4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                      CH.sub.3 CONH                                                                         H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                   5 W  4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                       C.sub.2 H.sub.5 OCONH                                                                 H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                   5 X  4-Cl-3-CH.sub.3 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                          H       H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                   5 Y  3-CH.sub.3 COOC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                            H       H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                   5 Z  3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                          H       H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                    5 AA                                                                              4-CH.sub.3 SC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                              H       H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                    5 AB                                                                              3-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                               H       H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                    5 AC                                                                              3-CH.sub.3 CONHC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                           H       H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                    5 AD                                                                               ##STR45##   H       H  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                    5 AE                                                                              CH.sub.3     H       H  C.sub.2 H.sub.5                                                                  C.sub.6 H.sub.5                                                                  CH.sub.3                                    5 AF                                                                              CH.sub.3     H       H  C.sub.2 H.sub.5                                                                  CH.sub.3                                                                         C.sub.6 H.sub.5                             5 AG                                                                              CH.sub.3     H       CH.sub.3                                                                         C.sub.2 H.sub.5                                                                  CH.sub.3                                                                         C.sub.6 H.sub.5 CH.sub.2 CH.sub.2          __________________________________________________________________________

EXAMPLE 5AH

Reaction of3,6(eq),9-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine(described in Example 1BJ) with methyl lithium in diethyl ether usingthe procedure described in Example 5A affords3,6(eq),9-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylbutyl)-2,6-methano-3-benzazocine.

EXAMPLE 6

A. Reaction of the3-[2-(4-fluorophenyl)ethyl]-8-ethoxycarbonylamino-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine(described in Example 5V) with aqueous alkali in ethanol affords3-[2-(4-fluorophenyl)ethyl]-8-amino-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine.

Following a procedure similar to that described in Example 6A, thefollowing 8-R₂ -6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁-11(eq)-(3-methyl-3-hydroxy-lower-alkyl)-2,6-methano-3-benzazocines offormula I are also prepared:

B.3-[2-(3-Hydroxyphenyl)ethyl]-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocineby alkaline hydrolysis of3-[2-(3-acetoxyphenyl)ethyl]-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine(described in Example 5X); and

C.3-[2-(3-Aminophenyl)ethyl]-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocineby alkaline hydrolysis of3-[2-(3-acetylaminophenyl)ethyl]-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine(described in Example 5AB).

EXAMPLE 7

A. Reaction of8-hydroxy-3,6(eq)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine(described in Example 5F) with acetic anhydride affords8-acetoxy-3,6(eq)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-acetoxybutyl)-2,6-methano-3-benzazocine.

Following a procedure similar to that described in Example 7A, using the3-methyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocinedescribed in Example 5A and an appropriate acid chloride in the presenceof pyridine, there are obtained the following3-methyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-R₇O-butyl)-2,6-methano-3-benzazocines of formula I in Table 7 where, ineach instance, R₁, R₅ and R₆ are CH₃ ; R₂, R₂ ', R₂ ", R₂ "', R₃ and R₈are each hydrogen; and R₄ is C₂ H₅.

                  TABLE 7                                                         ______________________________________                                        Example           R.sub.7                                                     ______________________________________                                        7B                C.sub.6 H.sub.5 CO                                          7C                4-CH.sub.3 C.sub.6 H.sub.4 CO                               7D                3-CH.sub.3 OC.sub.6 H.sub.4 CO                              7E                4-ClC.sub.6 H.sub.4 CO                                      7F                4-BrC.sub.6 H.sub. 4 CO                                     7G                4-FC.sub.6 H.sub.4 CO                                       7H                3-CF.sub.3 C.sub.6 H.sub.4 CO                               ______________________________________                                    

EXAMPLE 8

A. The3,6(eq)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinep-toluenesulfonate (15.9 g., 0.03 mole) described in Example 1H washydrolyzed to the free base, and the latter (10.5 g.) dissolved indiethyl ether was added to a stirred slurry of 600 mg. (0.005 mole) oflithium aluminum hydride in ether. The mixture was refluxed for onehour, quenched by the careful addition of 1.2 ml. of water in 10 ml. oftetrahydrofuran followed by excess dilute sodium hydroxide, filtered andthe filtrate evaporated to dryness. The residue (10 g.) was converted tothe p-toluenesulfonate salt which was recrystallized from ethanol/etherto give 6.2 g. of3,6(eq)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxyoctyl)-2,6-methano-3-benzazocinep-toluenesulfonate, m.p. 135°-137° C.

B. Reduction of 26.0 g. (0.075 mole) of ethyl3-[8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-11(eq)-yl]propionate(described in Lewis and Michne U.S. Pat. No. 4,148,794) with 3.6 g.(0.094 mole) of lithium aluminum hydride in 130 ml. of diethyl ether andisolation of the product in the form of the free base afforded 19.0 g.of8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxypropyl)-2,6-methano-3-benzazocine,which after several recrystallizations of a small sample from ethanolgave material having m.p. 128°-130° C.

C. Reduction of3-cyclopropylmethyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine(described in Example 1D) with lithium aluminum hydride in diethyl etherusing the procedure described in Example 8A affords3-cyclopropylmethyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxybutyl)-2,6-methano-3-benzazocine.

EXAMPLE 9

A. A solution of 4.72 g. (0.01 mole) of3-benzyl-6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine(described in Example 5E) in 50 ml. of DMF was reduced with hydrogenover 0.5 g. of palladium-on-charcoal under a hydrogen pressure of about50 p.s.i. When reduction was complete, the catalyst was removed byfiltration, and the solution, containing6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocinewas treated with 1.68 g. (0.02 mole) of sodium bicarbonate and 2.0 g.(0.015 mole) of cyclopropylmethyl bromide, and the mixture was warmedwith stirring on a steam bath for one hour.

The reaction mixture containing crude3-cyclopropylmethyl-6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine,was distilled at atmospheric pressure, collecting 25 ml. of distillate,and then treated with 2.1 g. (0.05 mole) of a 57% dispersion of sodiumhydride in mineral oil and 5 ml. of DMF. The mixture was cooled in anice bath and treated dropwise with stirring under nitrogen with 4.6 ml.of propanethiol. After refluxing and stirring for about four hours, thereaction mixture was poured into a solution of aqueous ammonium chlorideand extracted with 50 ml. of diethyl ether. The product was isolated inthe usual manner in the form of the free base which was recrystallizedfrom ethanol to give 2.4 g. of3-cyclopropylmethyl-6(eq)-methyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine,m.p. 195°-198° C. The methanesulfonate gave m.p. 232° C.

Following a procedure similar to that described in Example 9A, using anappropriate8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-3-benzyl-11(ax)-R₃-11(eq)-CH₂ Z-2,6-methano-3-benzazocine and an appropriate alkylatingagent, R₁ -Hal, (or reductive alkylation with formaldehyde and formicacid using the procedure described in Example 4C), there were obtainedthe 8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃-11(eq)-CH₂ Z-2,6-methano-3-benzazocines of formula I in Table 9 where,in each instance unless noted otherwise, R₂ is hydroxy; R₂ ', R₂ ", R₂"', R₇ and R₈ are each hydrogen; and R₄ is CH₃. Compounds for which novalue for R₆ is given are the ketones (Z is CH₂ COR₅). The compounds areotherwise the carbinols [Z is CH₂ C(R₅)(R₆)OH]. Melting points of theproducts are given in each case for the methanesulfonate salt, andyields are also given for the methanesulfonate unless noted otherwise.

                                      TABLE 9                                     __________________________________________________________________________    Example                                                                            R.sub.1 /R.sub.3                                                                         R.sub.5 /R.sub.6                                                                    Wt.S.M./Wt. Prod                                                                         m.p.(°C.)/Solv.                       __________________________________________________________________________    9 B  CH.sub.3   CH.sub.3                                                                            4.72 (HCl) 206-208                                           H          t-C.sub.4 H.sub.9                                                                   2.7        methanol/ether                               9 C  CH.sub.3   CH.sub.3                                                                            10.9 (base)                                                                              144-146                                           H          C.sub.3 H.sub.7                                                                     7.4 (base) acetone                                      9 D  C.sub.3 H.sub.5 --CH.sub.2 (a)                                                           CH.sub.3                                                                            2.5 (HCl)  249-252                                           CH.sub.3   t-C.sub.4 H.sub.9                                                                   1.4        methanol/ether                               9 E  C.sub.3 H.sub.5 --CH.sub.2 (a)                                                           CH.sub.3                                                                            9.2 (base) 182-183                                           H          C.sub.3 H.sub.7                                                                     1.8        ethanol/ether                                9 F  C.sub.3 H.sub.5 --CH.sub.2 (a)                                                           CH.sub.3                                                                            12.9 (base)                                                                              225-228                                           H (b)      t-C.sub. 4 H.sub.9                                                                  0.42       methanol/ether                               9 G  C.sub.3 H.sub.5 --CH.sub.2 (a)                                                           t-C.sub. 4 H.sub.9                                                                  3.4 (HCl)  266-268 (h)                                       CH.sub.3   CH.sub.3 (c)                                                                        1.4        methanol/ether                               9 H  CH.sub.3   t-C.sub. 4 H.sub.9                                                                  4.9 (HCl)  219-223 (base)                                    CH.sub.3   CH.sub.3                                                                            1.1 (base) ethyl acetate                                9 J  CH.sub.3   CH.sub.3                                                                            11.8 (HCl) 179-182 (base)                                    CH.sub.3   CH.sub.3                                                                            1.3 (base) ethyl acetate                                9 K  CH.sub.3   C.sub.4 H.sub.9                                                                     9.0 (HCl)  283-285 (HCl)                                     CH.sub.3   --    2.1 (HCl)  methanol/ether                               9 L  CH.sub.3   t-C.sub. 4 H.sub.9                                                                  4.7 (HCl)  190-195 (d)                                       CH.sub.3   --    1.5 (d)    ethanol/ether                                9 M  C.sub.3 H.sub.5 --CH.sub.2 (a)                                                           t-C.sub.4 H.sub.9                                                                   12.3 (HCl) 248-250 (CH.sub.3 SO.sub.3 H)                     H          CH.sub.3 (j)                                                                        1.3 (CH.sub.3 SO.sub.3 H)                                                                methanol/ether                               9 N  C.sub.3 H.sub.5 --CH.sub.2 (a)                                                           CH.sub.3                                                                            11.8 (HCl) 236-238 (HCl)                                     CH.sub.3   CH.sub.3                                                                            1.2 (HCl)  ethanol                                      9 P  C.sub.4 H.sub.7 --CH.sub.2 (e) (f)                                                       C.sub.5 H.sub.11                                                                    5.9 (HCl)  213-216 (HCl)                                     CH.sub.3   --    3.2 (HCl)  isopropanol                                  9 Q  CH.sub.3   t-C.sub. 4 H.sub.9                                                                  2.4 (HCl)  242-247 (g)                                       CH.sub.3   CH.sub.3                                                                            2.4 (CH.sub.3 SO.sub.3 H)                                                                methanol                                     9 R  CH.sub.3   t-C.sub. 4 H.sub.9                                                                  5.2 (HCl)  212-215                                           H          CH.sub.3                                                                            2.3 (CH.sub.3 SO.sub.3 H)                                                                methanol                                     __________________________________________________________________________      (a) Cyclopropylmethyl                                                         (b) R.sub.4 is C.sub.2 H.sub.5                                                (c) Isomeric with compound of Example 9D which was prepared via compound     of Example 5L. Compound of Example 9G prepared via compound of Example 1L      (d) Ethanesulfonate.                                                          (e) Cyclobutylmethyl                                                          (f) Debenzylated product reacted with 0.013 mole of cyclobutane              carboxylic acid chloride in chloroform in the presence of triethylamine,      and the resulting amide, without purification, converted to the ethylene      glycol ketal by reaction with ethylene glycol in the presence of              ptoluenesulfonic acid in toluene. The ketal was then reduced in               tetrahydrofuran with lithium aluminum hydride using the procedure of          Example 3A and the product, identical with the compound of Example 4F         isolated from an acid medium and then cleaved with sodium propylsulfide.       (g) Isomeric with the compound of Example 9H. Isomers both prepared by       reaction of methyl lithium with the same tbutyl ketone (R.sub.5 is            tC.sub.4 H.sub.9). Isomeric products, i.e. 3benzyl-6(eq),                     11(ax)dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eg)-(3-hydroxy-3,4,4-tr    methyl-pentyl)-2,6-methano-3-benzazocine, are readily separated from one       another in the crude product by conversion to the hydrochloride salt. One     isomeric form is insoluble in ethanol and gives rise to the isomer of         Example 9H. The other, much more soluble in ethanol, gives rise to the        isomer of Example 9Q. The isomer of Example 9Q predominates over that of      Example 9H when methyl lithium is reacted with the tbutyl ketone. The         opposite is true when tbutyl lithium is reacted with the methyl ketone        (R.sub.5 is CH.sub.3).                                                         (h) Samples of the free base were resolved into the two optical isomers      by treating the corresponding racemic des Ncyclopropyl methyl ether           (R.sub.1 is hydrogen and R.sub.2 is CH.sub.3 O) with d and 1 mandelic         acid. The former afforded the corresponding dbase.d mandelate (m.p.           163-166° C., from ethyl acetate) and the latter the corresponding      1base.1 mandelate (m.p. 162-165° C., from ethyl acetate).              Conversion of each of these to the free bases and conversion of the free      bases to the corresponding Ncyclopropylmethyl-8-hydroxy compounds using       the procedure described in Example 9A, and isolation of the products in       the form of the methanesulfonate salts afforded the respective                dbase.methanesulfonate, m.p. 279-282° C. (from methanol),              [α].sub.D.sup.25 = +61.0 and 1base.methanesulfonate, m.p.               281-285° C. (from methanol), [ α].sub.D.sup.25 =                 -61.3°.                                                                 (j) Isomeric with compound of Example 9A which was prepared via compound     of Example 1E. Compound of Example 9M was prepared via compound of Exampl     1K.                                                                      

EXAMPLE 10

Using a procedure similar to that described above in Example 9A, 3.19 g.(0.007 mole) of3-benzyl-6(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine(described in Example 5N) was debenzylated by reduction over 0.35 g. ofpalladium-on-charcoal and the resulting6(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocinereacted with 2.0 g. (0.015 mole) of cyclopropylmethyl bromide and 1.7 g.(0.020 mole) of sodium bicarbonate and the product isolated in the formof the hydrochloride salt to give 1.5 g. of3-cyclopropylmethyl-6(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocinehydrochloride, m.p. 232°-233° C. (from ethanol/ether).

EXAMPLE 11

A. A solution of 15 g. (0.04 mole) of3-benzyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine(described in Example 1E) was catalytically debenzylated and theresulting nor-base alkylated with cyclopropylmethyl bromide in thepresence of sodium bicarbonate using the procedure described in Example9A. The resulting3-cyclopropylmethyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine(12.9 g.) was dissolved in 125 ml. of toluene and added to 45 ml. of a2.1 M solution of n-butyl lithium in hexane at -65° C. using theprocedure described in Example 5A. The resulting3-cyclopropylmethyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocine(13.4 g.) was dissolved in 130 ml. of DMF and the ether group cleaved bytreatment with 7.1 g. (0.168 mole) of a 57% mineral oil dispersion ofsodium hydride and 12.8 g. (0.168 mole) of propanethiol in the mannerdescribed above in Example 9A. The product was converted to themethanesulfonate salt which was recrystallized from ethanol/ether togive 10.2 g. of3-cyclopropylmethyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocinemethanesulfonate, m.p. 184°-185° C.

Following a procedure similar to that described in Example 11A, usingthe3-benzyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinedescribed in Example 1E, ethyl lithium and an appropriate alkylatingagent, R₁ -Hal, (or reductive alkylation with formaldehyde and formicacid using the procedure described in Example 4C), there were obtainedthe 8-hydroxy-3-R₁-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylpentyl)-2,6-methano-3-benzazocinesof formula I in Table 11 where, in each instance, R₂ is hydroxy; R₂ ',R₂ ", R₂ "', R₃, R₇ and R₈ are hydrogen; R₄ and R₅ are CH₃ ; and R₆ isC₂ H₅. In each instance, the melting points are given for themethanesulfonate salt, and the yield of product is given for the freebase.

                  TABLE 11                                                        ______________________________________                                        Ex-                                                                           am-                                                                           ple  R.sub.1       Wt.S.M./Wt.Prod.                                                                            m.p.(°C.)/Solv.                       ______________________________________                                        11B  cyclopropyl--CH.sub.2                                                                       15.0 (base)   195-196                                                         8.3 (base)    acetone                                      11C  CH.sub.3      15.0 (base)   155.157                                                         11.0 (base)   ethanol                                      ______________________________________                                    

EXAMPLE 12

A. A 5.7 g. sample of3-methyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocinedescribed in Example 5G in DMF was cleaved with sodium propylsulfide(0.063 mole) using the procedure described in Example 9A and the product(3.4 g. of crude base) converted to the methanesulfonate salt which wasrecrystallized from ethanol/ether to give 2.6 g. of3-methyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocinemethanesulfonate, m.p. 184°-186° C.

Following a procedure similar to that described in Example 12A using anappropriate 8-methoxy-6(eq)-methyl-11(ax)-R₃ -1,2,3,4,5,6-hexahydro-3-R₁-11(eq)-CH₂ Z-2,6-methano-3-benzazocine, the following8-hydroxy-6(eq)-methyl-11(ax)-R₃ -1,2,3,4,5,6-hexahydro-3-R₁ -11(eq)-CH₂Z-2,6-methano-3-benzazocines of formula I were prepared where, in eachcase, R₂ ', R₂ ", R₂ "', R₇ and R₈ are hydrogen; R₄ is CH₃ ; and R₂ ishydroxy. Where no value for R₆ is given, the compound has the ketonestructure (Z is CH₂ COR₅) but otherwise has the carbinol structure [Z isCH₂ C(R₅)(R₆)OH].

                                      TABLE 12                                    __________________________________________________________________________    Example                                                                            R.sub.1 /R.sub.3                                                                    R.sub.5 /R.sub.6                                                                         Wt. S.M./Wt. Prod.                                                                      m.p.(°C.)/Solv.                        __________________________________________________________________________    12B  CH.sub.3                                                                            C.sub.5 H.sub.11                                                                         6.4 (base)                                                                              176-177 (a)                                        H     H          1.8 (a)   acetone                                       12C  C.sub.3 H.sub.5 --CH.sub.2                                                          C.sub.4 H.sub.9                                                                          5.0 (base)                                                                              235-237 (HCl)                                      CH.sub.3                                                                            --         2.5 (HCl) isopropanol                                   12D  CH.sub.3                                                                            CH.sub.2 CH.sub.2 --C.sub.3 H.sub.5                                                      6.2 (base)                                                                              128-130 (b)                                        CH.sub.3                                                                            --         0.9 (base)                                                                              ethyl acetate/hexane                          12E  CH.sub.3                                                                            (CH.sub.2).sub.2 CH(CH.sub.3).sub.2 (c)                                                  2.9 (HCl) 204-206                                            CH.sub.3                                                                            CH.sub.3   2.13 (CH.sub.3 SO.sub.3 H)                                                              methanol/ether                                12F  CH.sub.3                                                                            (CH.sub.2).sub.2 CH(CH.sub.2).sub.2 (d)                                                  3.15 (base)                                                                             238-241                                            CH.sub.3                                                                            CH.sub.3   1.48 (HCl)                                                                              ethanol/ether                                 __________________________________________________________________________      (a) pToluenesulfonate                                                         (b) The hydrochloride has m.p. 271-273° C. (from methanol/ether)       (c) Isomer I, prepared from Isomer I of Example 5S, and isomeric with        compound of Example 12F.                                                       (d) Isomer II, prepared from Isomer II of Example 5S, and isomeric with      compound of Example 12E.                                                 

EXAMPLE 13

A. A solution of 1.8 g. (0.0046 mole) of1-benzyl-3-(2-hydroxy-2-propyl)-5α-methyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolinehydrochloride was dissolved in 100 ml. of mesitylene and the solutiontreated with 3.8 ml. (0.1 mole) of formic acid and refluxed and stirredfor about twenty-four hours. On cooling, the mixture was extracted withthree 5 ml. portions of 1 M phosphoric acid, and the combined aqueousextracts washed twice with diethyl ether and then basified by thecautious addition of 6.6 g. of potassium hydroxide pellets. The oilwhich separated was extracted with diethyl ether, and the ether extractsworked up in the usual manner to give an oil which was converted to thehydrochloride salt. The latter was recrystallized from ethanol/ether togive 0.3 g. of3-benzyl-6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-2-butenyl)-2,6-methano-3-benzazocinehydrochloride, m.p. 232°-235° C.

B. Following a procedure similar to that described in Example 13A 19.6g. (0.062 mole) of1-methyl-3-(2-hydroxy-2-propyl)-5α-methyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolinein 1 liter of mesitylene and 38 ml. of formic acid was heated andstirred under reflux for twenty-four hours and worked up in the mannerdescribed in Example 13A to give 8.5 g. (0.028 mole) of3,6(eq)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eg)-(3-methyl-2-butenyl)-2,6-methano-3-benzazocineas an oil which, without further characterization, was cleaved with 0.15mole of sodium propylsulfide in 75 ml. of DMF using the proceduredescribed in Example 9A. The product was converted to themethanesulfonate salt which was recrystallized from ethanol to give 1.6g. of3,6(eq)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-2-butenyl)-2,6-methano-3-benzazocinemethanesulfonate, m.p. 226°-229° C.

Following a procedure similar to that described in Example 13A, using anappropriate 7-R₂ -1-R₁ -3-C(R₅)(R₆)OR₇ -4aα-R₃ -5α-R₄-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline in refluxingmesitylene/formic acid, there are obtained the respective 8-R₂ -6(eq)-R₄-1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃-11(eq)-(2-lower-alkenyl)-2,6-methano-3-benzazocines of formula I inTable 13 where, in each instance, R₂ ', R₂ ", R₂ "' and R₈ are hydrogen,and Z is --CH═CR₅ R₆.

                  TABLE 13                                                        ______________________________________                                        Example                                                                              R.sub.1        R.sub.2                                                                              R.sub.3                                                                            R.sub.4                                                                            R.sub.5                                                                            R.sub.6                           ______________________________________                                        13C    CH.sub.3       H      H    C.sub.3 H.sub.7                                                                    CH.sub.3                                                                           CH.sub.3                          13D    CH.sub.3       H      H    C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           CH.sub.3                          13E    CH.sub.3       H      H    CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                          13F    CH.sub.3       HO     H    C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           CH.sub.3                          13G    cyclopropyl-CH.sub. 2                                                                        H      H    C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           CH.sub.3                          13H    C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                            H      H    C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           CH.sub.3                          13J    CH.sub.3       H      H    C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           C.sub.3 H.sub.7                   13K    CH.sub.3       H      CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           CH.sub.3                          13L    CH.sub.3       H      H    C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           H                                 ______________________________________                                    

EXAMPLE 14

A. To a solution of 0.042 mole of diisopropylamide in hexane (preparedfrom 16.8 ml. of a 2.5 M solution of butyl lithium in hexane and 4.2 g.of diisopropylamine) was added a solution of 2.72 g. (0.02 mole) ofphenylacetic acid in 200 ml. of tetrahydrofuran (THF) over a twentyminute period while maintaining the temperature at 0° to -5° C. Themixture was stirred for about one hour at 0° C. and then treated with asolution of 3.45 g. (B 0.01 mole) of ethylβ-[3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine-11(eq)-yl]propionatein 25 ml. of THF. The mixture was stirred at ambient temperature forabout two hours, the solvent removed in vacuo and the residual gum wastreated with 30 ml. of dilute hydrochloric acid and 75 ml. of water. Themixture was refluxed with stirring for about an hour, poured onto ice,basified with 10% sodium hydroxide and extracted three times with ether.Washing of the combined extracts with saturated brine, drying overanhydrous magnesium sulfate and evaporation to dryness afforded 4.0 g.of an oil which was dissolved in acetone and treated with a solution ofmethanesulfonic acid in acetone. There was thus obtained 2.2 g. of3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3oxo-4-phenylbutyl)-2,6-methano-3-benzazocinemethanesulfonate, m.p. 189°-192° C.

B. Following a procedure similar to that described in Example 14A, 6.5g. (0.043 mole) of 3-methylphenylacetic acid was reacted with 0.096 moleof diisopropylamide (prepared from 47 ml. of a 2.0 M solution of n-butyllithium in hexane and 9.6 g. of diisopropylamine) and the resultinglithio salt reacted with 7.5 g. (0.022 mole) of ethylβ-[3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine-11(eq)-yl]propionatein 400 ml. of THF. The product was isolated in the form of the free baseto give 7.4 g. of3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-[3-oxo-4-(3-methylphenyl)butyl]-2,6-methano-3-benzazocineas an oil. A small amount was converted to the hydrochloride salt which,on repeated recrystallization from methanol/ether, afforded materialhaving m.p. 180°-181° C.

EXAMPLE 15

A solution of 5.0 g. (0.013 mole) of3,6(eq),11(ax)-trimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinehydrochloride, 1.25 g. (0.017 mole) of hydroxylamine hydrochloride and1.25 g. of sodium acetate in 50 ml. of ethanol and 10 ml. of water washeated on a steam bath for thirty minutes. The mixture was then cooledto room temperature and diluted with 100 ml. of water and the solidwhich separated was collected and dried to give 4 g. of crude productwhich was boiled with toluene for about an hour and then collected anddried to give 3.0 g. of3,6(eq),11(ax)-trimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocineoxime hyrochloride, m.p. 214°-216° C.

EXAMPLE 16

A. A solution of 6.9 g. (0.018 mole) of3,6(eq),11(ax)-trimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinehydrochloride, 2.1 g. (0.019 mole) of O-carboxymethylhydroxylaminehemihydrochloride and 5.2 g. (0.038 mole) of sodium acetate in 100 ml.of ethanol and 30 ml. of water was refluxed for about twelve hours,diluted with 50 ml. of hot water, and the solid which separated wascollected and dried to give 5.5 g. of3,6(eq),11(ax)-trimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocineO-carboxymethyloxime hydrate.

B. Following a procedure similar to that described in Example 16A, 7.96g. (0.02 mole) of3,6(eq),11(ax)-trimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-6-methylheptyl)-2,6-methano-3-benzazocinehydrochloride was reacted with 2.4 g. (0.02 mole) ofcarboxymethylhydroxylamine hemihydrochloride in 100 ml. of ethanol and30 ml. of water in the presence of 6.0 g. of sodium acetate to give 6.5g. of3,6(eq),11(ax)-trimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-6-methylheptyl)-2,6-methano-3-benzazocineO-carboxymethyloxime hydrate.

The preparation of the compounds of Formula I using the process of Lewisand Michne U.S. Pat. No. 4,119,628 and c.i.p. thereof, U.S. Pat. No.4,148,794 is illustrated by the following preparations in Examples17A-17AG, inclusive.

EXAMPLE 17

A. A solution of 24.5 g. (0.056 mole) of ethyl3-(1-oxo-3-cyclopropylpropyl)-7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylatein a solution of 1120 ml. of mesitylene and 42 ml. of formic acid wasstirred and refluxed at 117° C. for twenty-four hours. The mixture wasextracted with 420 ml. of water and 60 ml. of dilute hydrochloric acid,the organic layer washed with water, and the combined aqueous layersextracted once with diethyl ether and basified with 35% sodiumhydroxide. Extraction of the aqueous layer with diethyl ether, washingthe ether extracts first with water, then with brine, drying andevaporation to dryness afforded 5.3 g. of an oil which was dissolved inethanol and treated with ethereal hydrogen chloride. There was thusobtained 4.6 g. of3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-5-cyclopropylpentyl)-2,6-methano-3-benzazocinehydrochloride, m.p. 224°-226° C. whose preparation is also describedabove in Example 1 AG.

Following a procedure similar to that described in Example 17A, using anappropriate lower-alkyl 1-R₁ -3-R₅ CO-4aα-R₃ -5α-R₄ -7-R₂-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylateof formula IX, which are described in Lewis and Michne U.S. Pat. No.4,119,628 and c.i.p. thereof U.S. Pat. No. 4,148,794, there wereprepared the 3-R₁ -6(eq)-R₄ -11(ax)-R₃ -1,2,3,4,5,6-hexahydro-11(eq)-CH₂CH₂ COR₅ -2,6-methano-3-benzazocines of formula I in Table 17 where, ineach instance, R₂ ', R₂ " and R₂ "' are hydrogen and Z is CH₂ COR₅. TheExample numbers where the alternative preparations of the same speciesfrom the 7-R₂ -1-R₁ -3-COR₅ -4aα-R₃ -5α-R₄-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolines of formulaII have been described above are given in parentheses in the columnheaded "Example". The reaction conditions used, that is procedure Adescribed in Example 1A using trimethylammonium formate or procedure Bdescribed in Example 1B using formic acid in refluxing mesitylene, arealso indicated in the column headed "Example" by the respectivedesignations A and B.

                                      TABLE 17                                    __________________________________________________________________________                              Wt. S.M.  M.P. (°C.)                         Example                                                                             R.sub.1 /R.sub.2                                                                   R.sub.3 /R.sub.4                                                                   R.sub.5   Wt. Prod. Solv.                                     __________________________________________________________________________    17 B(1AA)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3  57.1 (base)                                                                             183-186                                   B     CH.sub.3 O                                                                         CH.sub.3       6.6 (HCl) ethanol/ether                             17 C(1U)                                                                            C.sub.6 H.sub.5 CH.sub.2                                                           CH.sub.3                                                                           (CH.sub.2).sub.4 CH.sub.3                                                               139.9 (base)                                                                            223-227                                   B     CH.sub.3 O                                                                         CH.sub.3       35.9 (HCl)                                                                              ethanol/ether                             17 D(1AB)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           (CH.sub.2).sub.4 CH.sub.3                                                               24.1 (base)                                                                             oil (b)                                   B     H    CH.sub.3       17.8 (base)                                         17 E(1AR)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           (CH.sub.2).sub.4 CH.sub.3                                                               7.0 (base)                                                                              225-227.5                                 B     CH.sub.3 O                                                                         C.sub.2 H.sub.5                                                                              4.1 (HCl) acetone/ether                             17 F(1AC)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                     27.9 (base)                                                                             oil (c)                                   B     H    CH.sub.3       20.7 (base)                                         17 G(1AS)                                                                           C.sub.6 H.sub.5 CH.sub.2                                                           CH.sub.3                                                                           (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                     75.9 (base)                                                                             oil                                       B     CH.sub.3 O                                                                         CH.sub.3       57.1 (base)                                         17 H(1AD)                                                                           CH.sub.3                                                                           H    (CH.sub.2 ).sub.2 CH(CH.sub.3).sub.2                                                    28.3 (base)                                                                             159-162.5 (d)                             B     CH.sub.3 O                                                                         CH.sub.3       9.8 (oxalate)                                                                           ethanol/ether                             17 J(1AT)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                     31.2 (base)                                                                             250-252                                   B     CH.sub.3 O                                                                         C.sub.2 H.sub.5                                                                              7.3 (HCl) ethanol/ether                             17 K(1AF)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           (CH.sub.2).sub.3 CH(CH.sub.3).sub.2                                                     23.7 (base)                                                                             197-200                                   B     CH.sub.3 O                                                                         CH.sub.3       8.2 (HCl) ethanol/ether                             17 L(1AE)                                                                           CH.sub.3                                                                            ##STR46##                                                                         (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                     13.5 (base)                                                                             169-173                                   B     CH.sub.3 O          6.6 (HCl) (1/2 H.sub.2 O)                                                               ethanol/ether                             17 M(1AH)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2 cyclobutyl                                                                     20 (base) oil (e)                                   A     CH.sub.3 O                                                                         CH.sub.3       8.9 (base)                                          17 N(1AJ)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           (CH.sub.2).sub.2 cyclopentyl                                                            43.7 (base)                                                                             219-223                                   B     CH.sub.3 O                                                                         CH.sub.3       19.5 (HCl)                                                                              ethanol/ether                             17 P(1AK)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           (CH.sub.2).sub.2 cyclopentyl                                                            20.6 (base)                                                                             231-235 (a)                               B     H    CH.sub.3       8.5 (H.sub.2 SO.sub.4)                                                                  ethanol/ether                             17 Q(1AM)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           C.sub.6 H.sub.5                                                                         21.6 (base)                                                                             94-97                                     B     H    CH.sub.3       6.0 (base)                                                                              ethanol                                   17 R(1AN)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           C.sub.6 H.sub.5                                                                         35.2 (base)                                                                             102-106                                   B     CH.sub.3 O                                                                         CH.sub.3       14.8 (base)                                                                             ethanol                                   17 S(1AP)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           C.sub.6 H.sub.4 CH.sub.3 (3)                                                            12.6 (base)                                                                             94-96                                     A     CH.sub.3 O                                                                         CH.sub.3       6.9 (base)                                                                              methanol                                  17 T(1AQ)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           C.sub.6 H.sub.4 CH.sub.3 (4)                                                            4.0 (base)                                                                              87-89                                     A     CH.sub.3 O                                                                         CH.sub.3       2.1 (base)                                                                              methanol                                  17 U(1AV)                                                                           CH.sub.3                                                                           CH.sub.3                                                                           (CH.sub.2).sub.2 cyclobutyl                                                             12.4 (base)                                                                             153-155                                   A     CH.sub.3 O                                                                         CH.sub.3       8.3 (CH.sub.3 SO.sub.3 H)                                                               acetone/ether                             17V   CH.sub.3                                                                           CH.sub.3                                                                           CH(CH.sub.3).sub.2                                                                      10.0 (base)                                                                             211-214                                   A     CH.sub.3 O                                                                         CH.sub.3       5.6 (CH.sub.3 SO.sub.3 H)                                                               acetone                                   17W   CH.sub.3                                                                           CH.sub.3                                                                           cyclopentyl                                                                             11.5 (base)                                                                             138-141                                   A     CH.sub.3 O                                                                         CH.sub.3       7.3 (CH.sub.3 SO.sub.3 H)                                                               acetone/ether                             17X   CH.sub.3                                                                           CH.sub.3                                                                           (CH.sub.2).sub.2 cyclobutyl                                                             12.4 (base)                                                                             153-155                                   A     CH.sub.3 O                                                                         CH.sub.3       8.3 (CH.sub.3 SO.sub.3 H)                                                               acetone/ether                             17Y   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2 cyclobutyl                                                                     20 (base) 166-168                                   A     CH.sub.3 O                                                                         CH.sub.3       5.2 (CH.sub.3 SO.sub.3 H)                                                               acetone/ether                             17Z   C.sub.6 H.sub.5 CH.sub.2                                                           CH.sub.3                                                                           (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                     52 (base) 228-230                                   A     CH.sub.3 O                                                                         CH.sub.3       22.5 (HCl)                                                                              ethanol                                   17AA  C.sub.6 H.sub.5 CH.sub.2                                                           CH.sub.3                                                                           (CH.sub.2).sub.4 CH.sub.3                                                               96.8 (base)                                                                             oil                                             CH.sub.3 O                                                                         CH.sub.3       75.3 (base)                                         17AB  CH.sub.3                                                                           CH.sub.3                                                                           cyclopropyl                                                                             47.7 (base)                                                                             128.5-131.5                               A     CH.sub.3 O                                                                         CH.sub.3       3.6 (base)                                                                              ethanol                                   17AC  CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                     50.4 (base)                                                                             220-221                                   A     CH.sub.3 O                                                                         C.sub.2 H.sub.5                                                                              2.0 (HCl) acetone/ether                             17AD  CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    (CH.sub.2).sub.4 CH.sub.3                                                               41.5 (base)                                                                             198-199                                   B     CH.sub.3 O                                                                         C.sub.2 H.sub.5                                                                              6.9 (HCl) ethanol/ether                             17AE  CH.sub.3  (CH.sub.2).sub.4 CH.sub.3                                                               49.1 (base)                                                                             oil                                                   ##STR47##                                                         A     CH.sub.3 O          19.3 (base)                                         17AF  CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    (CH.sub.2).sub.4 CH.sub.3                                                               42.3 (base)                                                                             164-167                                   A     CH.sub. 3 O                                                                        CH.sub.3       2.1 (p-tosylate)                                                                        ethanol/ether                             17AG  CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2 cyclopentyl                                                                    70.9 (base)                                                                             242-245                                   B     CH.sub.3 O                                                                         CH.sub.3       37.3 (HCl)                                                                              ethanol/ether                             __________________________________________________________________________     (a) The free base was obtained as an amber oil.                               (b) The H.sub.2 SO.sub.4 salt gave m.p. 191-193° C.                    (c) The H.sub.2 SO.sub.4 salt gave m.p. 190-196° C.                    (d) The ptosylate salt gave m.p. 131-135° C.                           (e) The methanesulfonate gave m.p. 166-168° C.                    

The β-keto esters of formula IX, which are required as startingmaterials for each of Examples 17AB through 17AG are not specificallydisclosed in U.S. Pat. No. 4,148,794. The species required for Examples17AB through 17AG were prepared according to the procedure described inU.S. Pat. No. 4,148,794 by reaction of an appropriate ethyl7-methoxy-1-methyl-4aα-R₃ -5α-R₄-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylatewith lithium diisopropylamide in tetrahydrofuran and reaction of theresulting lithium salt with an appropriate acid chloride (R₅ COCl).These β-keto esters of formula IX used as starting materials forExamples 17AB through 17AG are given in Examples 17ABa through 17AGa,respectively, in Table 17a below where the values for R₁, R₂, R₃, R₄ andR₅ have the corresponding meanings given in Table 17 above, and wherethe weights of starting materials are given for the ethyl7-methoxy-1-methyl- 4aα-R₃ -5α-R₄-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.

                  TABLE 17a                                                       ______________________________________                                        Example      Wt. S.M.     Wt. Prod.                                           ______________________________________                                        17ABa        60.0         51.2 (base)-oil                                     17ACa        50.0         50.4 (base)-oil                                     17ADa        42.0         41.5 (base)-oil                                     17AEa        47.8         51.0 (base)-oil                                     17AFa        40.0         42.3 (base)-oil                                     17AGa        60.0         70.9 (base)-oil                                     ______________________________________                                    

EXAMPLES 17AH-17AL

Certain species of the compounds of formula I were prepared by reactionof ethyl3-[8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-11(eq)-yl]propionate(hereinafter referred to as the "propionate ester") with a twenty molarpercent excess of lithium diisopropylamide (prepared by reaction ofbutyl lithium with diisopropylamine) and reaction of the resultinglithium salt with a molar excess of an appropriate acid chloride,followed by decarboxylation of the resulting β-keto ester by heating thelatter, as before, in trimethylammonium formate. There were thusprepared the following compounds of formula I:

Example17AH--3,6(eq),11(ax)-Trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(4,4-dimethyl-3-oxooctyl)-2,6-methano-3-benzazocinepicrate (3.0 g., m.p. 136°-139° C. from ethanol) prepared by reacting9.6 g. (0.028 mole) of the propionate ester with 0.033 mole of lithiumdiisopropylamide in 200 ml. of tetrahydrofuran; reacting the resultinglithium salt with 7.9 g. (0.049 mole) of α,α-dimethylhexanoyl chloride;and boiling a solution of 5.2 g. (0.011 mole) of the resulting β-ketoester in 25 ml. of trimethylammonium formate for twelve minutes;

Example17AJ--3,6(eq),11(ax)-Trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(4,4-dimethyl-3-oxohexyl)-2,6-methano-3-benzazocinemethanesulfonate (3.1 g., m.p. 200°-202° C. from acetone) prepared byreacting 14.1 g. (0.041 mole) of the propionate ester with 0.052 mole oflithium diisopropylamide in 275 ml. of tetrahydrofuran; reacting theresulting lithium salt with 8.2 g. (0.061 mole) of α,α-dimethylbutyrylchloride; and boiling a solution of 20.5 g of the resulting β-keto esterin 100 ml. of trimethylammonium formate for eighteen minutes;

Example 17AK--3,6(eg),11(ax)-Trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(4,4-dimethyl-3-oxoheptyl)-2,6-methano-3-benzazocine picrate (10.7g., m.p. 183°-187° C. from ethanol) prepared by reacting 15.8 g. (0.046mole) of the propionate ester with 0.055 mole of lithiumdiisopropylamide in 400 ml. of tetrahydrofuran; reacting the resultinglithium salt with 11.6 g. (0.078 mole) of α,α-dimethylpentanoylchloride; and boiling a solution of 19.8 g. (0.046 mole) of theresulting β-keto ester in 100 ml. of trimethylammonium formate.

Example17AL--3,6(eq),11(ax)-Trimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-cyclopropyl-3-oxopropyl)-2,6-methano-3-benzazocine(8.0 g. as an oil) prepared by reaction of 5.5 g. (0.015 mole) of ethyl3-[8-methoxymethoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-11(eg)-yl]propionatewith 0.018 mole of lithium diisopropylamide in 150 ml. oftetrahydrofuran; reacting the resulting lithium salt with 2.8 g. (0.027mole) of cyclopropanecarbonyl chloride; and boiling the resulting β-ketoester in 70 ml. of trimethylammonium formate.

EXAMPLE 18

A mixture of about 0.047 mole of methylβ-[3,6(eq),11(ax)-trimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine],350 ml. of methylene dichloride, 125 ml. of dimethoxymethane and 0.5 ml.of ethanesulfonic acid was heated under reflux under a Soxhlet extractorcontaining 4A molecular sieves for twenty-seven hours. The reactionmixture was then filtered into a mixture of 50 ml. of 2.5 N sodiumhydroxide and 250 g. of ice, and the solid which separated was collectedand air-dried to give 10.4 g. of recovered starting material. Thefiltrate was extracted two times with methylene dichloride, and thecombined extracts, on drying and evaporation to dryness, afforded 9.2 g.of methylβ-[3,6(eq),11(ax)-trimethyl-8-methoxymethoxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-11(eq)-yl]propionateas an oil.

A solution of the latter (5.5 g., 0.015 mole) in 150 ml. oftetrahydrofuran (THF) was added to a solution of lithiumdiisopropylamide [prepared from 7.9 ml. of a 2.3 M solution of butyllithium and 1.8 g. (0.018 mole) of diisopropylamine in tetrahydrofuran]while maintaining the temperature at -70° C., and the mixture wasstirred for thirty minutes. The resulting solution was treated with asolution of 2.8 g. (0.027 mole) of cyclopropanecarbonyl chloride in THFadded over a period of one minute. The solution was then stirred forthirty minutes and poured into 200 ml. of saturated aqueous sodiumbicarbonate. The mixture was extracted with diethyl ether, and the etherextracts were washed with saturated sodium chloride, dried overanhydrous magnesium sulfate and evaporated to dryness to give 8 g. of anoil which was boiled for eleven minutes with 10 ml. of trimethylammoniumformate. The mixture was concentrated to about 35 ml. in vacuo, and theresidue was suspended in water, the pH adjusted to 8.0 and extractedwith methylene dichloride. Work-up of the organic extracts as beforeafforded 5.1 g. of an oil which was suspended in 100 ml. of ethanol and10 ml. of 5% potassium hydroxide and refluxed overnight. The mixture wasagain adjusted to pH 8, concentrated under reduced pressure andextracted again with methylene dichloride. Evaporation of the extractsto dryness afforded 4.0 g. of crude product which was converted to themethanesulfonate which, on recrystallization from isopropanol, afforded1.8 g. of3,6(eq),11(ax)-trimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-cyclopropyl-3-oxopropyl)-2,6-methano-3-benzazocinemethanesulfonate, m.p. 213°-215° C.

EXAMPLE 19

A solution of 5.0 g. (0.015 mole) of ethylβ-[3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-11(eq)-yl]propionatein 25 ml. of toluene was cooled in an acetone/dry ice bath and treatedwith 10 ml. of a 1.6 M solution of t-butyl lithium in pentane over aperiod of about thirty minutes under a nitrogen atmosphere. The mixturewas then stirred for an additional thirty minutes, allowed to warm toambient temperature and then poured into a solution containing 50 g. ofammonium chloride in 100 ml. of water. The mixture was extracted twotimes with ether, the combined extracts were washed with saturatedbrine, dried over magnesium sulfate and evaporated to dryness to give 6g. of an oil which was refluxed in a solution of 50 ml of ethanol and 50ml. of 5% potassium hydroxide for about forty-eight hours. Extraction ofthe mixture with ether and work-up of the ether extracts as beforeafforded 5.3 g. of an oil which was dissolved in acetone and treatedwith methanesulfonic acid to give 2.4 g. of3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eg)-(4,4-dimethyl-3-oxopentyl)-2,6-methano-3-benzazocinemethanesulfonate, m.p. 174°-176°.

EXAMPLE 20

Following a procedure similar to that described in Example 18, 15.4 g.(0.045 mole) of ethylβ-[3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-11(eq)-yl]propionatewas converted to the lithium salt by reaction of the former with aslight molar excess of lithium diisopropylamide in THF, and theresulting lithium salt was treated with 12.9 g. (0.078 mole) of1-bromohexane. There was thus obtained 14.9 g. of ethylα-hexyl-β-[3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-11(eq)-yl]propionateas an oil. The picrate salt gives m.p. 175°-177° C. (from ethanol).

The latter (7.0 g., 0.016 mole), dissolved in 60 ml. of THF, was addedto a solution of 20 ml. of a 1.9 M solution of methyl lithium in diethylether under a nitrogen atmosphere while maintaining the temperature at0° C. When addition was complete the mixture was stirred at ambienttemperature for four hours, then poured into aqueous bicarbonate, andthe mixture extracted with diethyl ether. Isolation of the product fromthe ether extracts as before afforded 7.8 g. of3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-{3-[2-(2-hydroxy)propyl]octyl}-2,6-methano-3-benzazocineas an oil. The methanesulfonate gave m.p. 164°-166° C. (from acetone).

The latter (3.2 g., 0.006 mole) was cleaved with sodium propylsulfide in100 ml. of DMF using the procedure described above in Example 9A. Theproduct was isolated in the form of the methanesulfonate to give 1.6 g.of3,6(eq),11(ax)-trimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-{3-[2-(2-hydroxy)propyl]octyl}-2,6-methano-3-benzazocinemethanesulfonate, m.p. 192°-195° C. (from methanol).

EXAMPLE 21

A mixture of 3.3 g. (0.008 mole) of 3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-{3-[2-(2-hydroxy)propyl]octyl}-2,6-methano-3-benzazocine(described in Example 20) in 10 ml. of acetic anhydride containing 0.8g. of methanesulfonic acid was boiled for ten minutes, then concentratedto a small volume, basified with aqueous sodium hydroxide, boiled forseveral more minutes, then cooled, extracted and the dried extractstaken to dryness to give 3.2 g. of an oil which was dissolved in acetoneand treated with methanesulfonic acid. There was thus obtained, afterseveral recrystallizations from acetone, 1.2 g. of3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-{2-[2-(1-propenyl)]octyl}-2,6-methano-3-benzazocinemethanesulfonate, m.p. 176°-178° C.

EXAMPLE 22

A mixture containing 1.6 g. of a 50% mineral oil suspension of sodiumhydride (0.033 mole) in 30 ml. of dimethylsulfoxide (DMSO) was heated at70°-80° C. until no further gas was given off. The mixture was thencooled to ambient temperature, treated with 11.7 g. (0.033 mole) ofmethyl triphenyl phosphonium bromide in 35 ml. of DMSO, and the mixturewas stirred for one-half hour at ambient temperature. The mixture thusprepared was treated with a solution of 8.0 g. (0.022 mole) of3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(6-methyl-3-oxo-heptyl)-2,6-methano-3-benzazocinein 35 ml. of DMSO, and the mixture was stirred at ambient temperatureunder a nitrogen atmosphere for about forty-eight hours and then pouredinto 200 ml. of water. The resulting mixture was extracted three timeswith water, washed with saturated brine, dried over magnesium sulfateand concentrated to dryness to give a waxy solid, which was dissolved ina 60:40:2 mixture of hexane:ether:isopropanol and chromatographed on 200g. of an activated silica gel column, the product being eluted with thesame solvent system. The first 300 ml. of eluate were discarded, and thenext 1,200 ml. were combined and taken to dryness to give 3.5 g. of3,6(eq),11(ax)-trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-[3-(3-methylbutyl)-3-butenyl]-2,6-methano-3-benzazocine.

The latter was cleaved with 0.048 mole of sodium propylsulfide in 70 ml.of DMF using the procedure described above in Example 9A. The productwas isolated in the form of the methanesulfonate to give 2.4 g. of3,6(eq),11(ax)-trimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-[3-(3-methylbutyl)-3-butenyl]-2,6-methano-3-benzazocinemethanesulfonate, m.p. 231°-235° C.

EXAMPLE 23

A solution of 3.0 g. (0.0064 mole) of 3,6(eq),11(ax)-trimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocineethanesulfonate and 1.5 ml. of acetic anhydride in 25 ml. of pyridinewas stirred at ambient temperature for three and one-half hours, thenpoured into a mixture of 100 ml. of ether and 100 ml. of dilute sodiumhydroxide. The organic layer was separated, the aqueous layer wasextracted twice with ether, and the combined ether extracts were washedtwice with water, dried over magnesium sulfate and taken to dryness togive 2.7 g. of a gum, which was dissolved in acetone and treated with amolar excess of methanesulfonic acid. Several recrystallizations of theresulting solid from acetone/ether afforded 2.0 g. of3,6(eq),11(ax)-trimethyl-8-acetoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinemethanesulfonate, m.p. 189°-190° C.

EXAMPLE 24

Following a procedure similar to that described in Example 18, asolution of 4.2 g. (0.004 mole) of3,6(eq),11(ax)-trimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinein 4.0 ml. of dimethoxymethane and 65 ml. of methylene dichloridecontaining a catalytic amount of ethanesulfonic acid was refluxed undera Soxhlet extractor containing 4A molecular sieves and the productisolated in the form of the free base to give 1.75 g. of3,6(eq),11(ax)-trimethyl-8-methoxymethoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocineas a waxy solid, m.p. 46°-48° C.

BIOLOGICAL TEST RESULTS

The compounds of formula I are generally active in theacetylcholine-induced abdominal constriction test (Ach), a primaryanalgesic screening test, and also in either the rat tail flick radiantthermal heat analgesic test (Tail Flick Agon.) or the rat tail flickphenazocine antagonist test (Phen.). Some of the species have also beentested and found active in the phenyl-p-quinone-induced writhing (PPQ)and anti-bradykinin (BK) tests, which are also primary analgesicscreening procedures.

Data so obtained for the compounds, identified by reference to thepreceding examples and expressed either in terms of the ED₅₀ (mg./kg.,subcutaneous administration) or in terms of percent inhibition, aregiven below. Where more than one form of a given species has beendescribed in the examples, such as the free base, or a particular saltform or a d- or l-form, if resolution into optical isomers was carriedout, the compounds are so-identified along with the example number.

The finding of inactivity in a given test is indicated by the letter I.All doses are expressed in milligrams per kilogram (mg./kg.).

    __________________________________________________________________________                                       Tail Flick                                 Example   Ach  Phen. PPQ    BK     Agonist                                    __________________________________________________________________________    1A        1.7  I     --     --     14 ± 2                                  1B        0.3  I     --     --     6.9 ± 0.8                               1C        1.1  --    --     --     11 ± 1.0                                1D        7.4  24    64%/50 --     I                                          1H        18   I     --     40%/10 I/240                                      1M        1.9  I     --     --     5.9 ± 0.95                              1N        0.89 I     --     --     2.0 ± 0.22                              1P        87%/75                                                                             7.8   --     --     I                                                    33%/25                                                              1Q        ˜6.9                                                                         I     --     --     16%/120                                                                       14%/10                                     1S        1.0  I     --     --     4.3 ± 0.52                              1U        53%/75                                                                             I     --     --     I                                                    43%/25                                                                        7%/7.5                                                              1V        2.0  I     --     2.4    16 ± 3.3                                1W        60%/75                                                                             I     --     --     I                                                    20%/25                                                              1Y        0.63 I     --     --     1.35                                       1Z        11   21    --     --     I                                          1AA,17B   3.5  --    --     --     66%/120                                    1AB,17D   ˜1.9                                                                         I/1.0,10,80                                                                         --     --     16                                         1AC,17F   ˜1.3                                                                         I/1.0,10,80                                                                         --     --     15                                         1AD,17H   11   I/80  --     --     13%/120                                    1AE,17L   1.2  I/80  --     --     31                                         1AF,17K   7.5  190 --                                                                              --     70%/120                                                                              24%/60                                                                        9%/30                                      1AG,17A   1.3  I/80  --     --     9.4                                        1AH       ˜0.71                                                                        I/1.0 --     --     2.6                                        1AJ,17N   10   26%/80                                                                              --     --     33%/240                                                                       12%/120                                    1AK,17P(H.sub.2 SO.sub.4)                                                               5.6  I/80  --     28     16%/120                                    1AK(base) 60%/75                                                                             I/80  --     --     I/120,240                                            47%/25                                                                        33%/10                                                              1AL,14A   ˜0.22                                                                        I/0.1-1.0,10                                                                        --     --     0.86                                       1AM,17Q   0.081                                                                              I/0.1-1.0,10                                                                        --     --     0.28                                       1AN,17R   0.025                                                                              I/0.01-0.1                                                                          --     --     0.18                                       1AP,17S   0.24 I/0.1 --     --     0.46                                       1AQ,17T   0.90 I/0.1 --     --     1.5                                        1AV       5.6  I/80  --     I/10   19%/60                                                                 80%/20 48%/120                                                                       43%/240                                    2B        1.4  I     --     0.24   42 ± 21                                 2C        ˜0.18                                                                        I     --     --     0.99 ± 0.14                             2D        0.023                                                                              I     --     --     0.099 ± 0.014                           2E        0.19 I     --     --     0.95 ± 0.11                             2F(d,1-HCl)                                                                             0.074                                                                              0.30  0.018  0.15                                              2F(d-HCl) 13%/10                                                                             I     --     --     I                                                    27%/1.0                                                                       27%/0.5                                                             2F(1-HCl) 0.016                                                                              ˜0.088                                                                        --     --     9%/120                                     2F(d,1-CH.sub.3 SO.sub.3 H)                                                             0.049                                                                              --    --     --     --                                         2G        12   0.04  --     2.2    16                                         2H(d,1-HCl)                                                                             0.24 0.008(a)                                                                            0.28   0.043  I                                                    26(p.o)                                                                            7.8(p.o.)                                                      2H(d,1-CH.sub. 3 SO.sub.3 H)                                                            0.23 --    --     --     --                                         2H(l-CH.sub. 3 SO.sub.3 H)                                                              0.74 0.005 0.052  0.022  I/95                                                 0.19                                                                2H(d-CH.sub. 3 SO.sub.3 H)                                                              6.3  I/80  5.6    I/50   I/85                                                 ˜ 11                                                          2H(napsylate)                                                                           0.10 ˜2(i.p.)                                                                      --     --     --                                         2J        0.019                                                                              I     --     --     0.067                                      2K        0.24 I     --     --     1.5                                        2L(CH.sub.3 SO.sub.3 H)                                                                 8.1  0.015 --     0%/10,50                                                                             I                                          2L(C.sub.2 H.sub.5 SO.sub.3 H)                                                          14   I/80  --     I/100  --                                         2M(base)  0.25 --    --     100%/0.5                                                                             70%/60                                     2M(CH.sub.3 SO.sub.3 H)                                                                 0.17 --    0.21   0.19   2.5                                        2N        4.2  0.42  --     --     I/120                                      2R        5.3  0.029 --     --     I/120                                      2S        0.15 1.1   --     --     13%/120                                    2U        0.066                                                                              0.86  --     --     59%/120                                                                       36%/60                                                                        19%/30                                     2V(d,1-H.sub. 2 SO.sub.4)                                                               60%/75                                                                             0.012 --     0%/25  I/100                                                47%/25                                                              2V(d-CH.sub. 3 SO.sub.3 H)                                                              87%/75                                                                             ˜0.43                                                                         --     --     --                                         2W        0.0012                                                                             --    --     --     0.00135                                    2X        0.0036                                                                             I/0.001                                                                             --     --     0.0046                                     2Y        0.011                                                                              I/0.01                                                                              --     --     0.028                                      2Z        1.3  ˜0.004                                                                        --     0.28   I/120                                      2AA       8.2  0.0052                                                                              --     --     I/120                                      2AB       11   I/80  --     0.12   11,24                                                22(p.o.)                 40%/60                                                                        58%/120                                                                       53%/240                                    2AD       1.9  0.016 --     --     I/120                                      2AE       0.0055                                                                             I/0.001-1.0                                                                         --     --     0.044                                      2AF       0.27 0.56                20%/120                                    2AJ       0.029                                                                              0.065 --     --     13%/1.0                                                                       34%/10                                                                        14%/40                                                                        21%/120                                    2AK       12   4.5   --     --     I/120                                      2AL       4.8  1.9   --     --     I/120                                      2AM       9.2  3.7   --     --     --                                         3C        13   I     --     I/50   40%/60(i.p.)                                                           100%/50(i.p.)                                     3D        2.7  I     --     --     25%/30                                     3G(HCl)   13%/25                                                                             I     --     --     40%/120(i.p.)                                        13%/2.5                  33%/60(i.p.)                               3G(base)  8.9  I/80  --     --     I/120                                      3H        100%/75                                                                            I     --     --     I                                                    27%/25                                                              3J        16   I/80  --     --     I/60,120                                   4A        8.9  0.088 --     --     I/120                                      4C        6.9  I     --     --     64 ± 12                                 4D        5.4  I     --     --     17%/120                                                                       64%/240                                    4E(HCl)   1.5  I     --     --     30 ± 7.4                                4F        13%/75                                                                             I     --     --     I                                                    7%/25                                                               4H        7%/75                                                                              I     --     --     I                                                    13%/25                                                              4J        87%/75                                                                             0.013 --     --     I/120                                                47%/25                                                              4K        7.5  0.037 --     --     I/120                                      4L        27%/75                                                                             0.0078                                                                              --     --     I/120                                                27%/25                                                              4M        5.1  0.026 --     --     I/120                                      4N        40%/75                                                                             0.011 --     --     I/240                                                27%/25                                                              5A        1.6  I     --     --     11 ± 2.2                                5B        2.1  I     --     --     10%/60                                     5C        4.7  61%/80                                                                              11     --     I                                          5D        16   0.046 21     40%/100                                                                              I                                                                      25%/50                                                                        40%/10                                            5F        8.2  I     5.9    --     I                                          5S        3.9  I/10  --     I/10   --                                         8A        2.8  I     --     --     60 ± 6.9                                8B        0.68 I/10  --     17     23                                         9A        93%/75                                                                             0.27  --     --     --                                                   33%/25                                                                        27%/10                                                              9B        40%/75                                                                             I     --     --     I                                                    27%/25                                                              9C        2.6  I     --     --     68 ± 14                                 9D        67%/75                                                                             0.022 --     --     I                                                    33%/25                                                                        13%/1.0                                                             9E        7.6  0.019 --     --     I                                          9F        34   0.47  --     --     I                                          9G(d,1-CH.sub. 3 SO.sub.3 H)                                                            8.9  0.71  --     I/28   I                                          9G(1-CH.sub. 3 SO.sub.3 H)                                                              3.8  0.34  --     --     I                                          9H        100%/75                                                                            I     --     --     I                                                    47%/25                                                              9J        3.8  2.3   --     7.9    I                                          9K        0.017                                                                              I     --     0.012  0.039 ± 0.006                           9L        6.6  2.4   --     ˜5                                                                             I                                          9M        9.0  1.1   --     --     I/15                                       9N        4.5  0.006 --     --     I                                          9P        20%/75                                                                             0.26  --     --     I/120(i.p.)                                          27%/25                                                              9Q        100%/75                                                                            0.33  --     --     I                                                    47%/25                                                              9R        87%/75                                                                             I     --     --     I                                                    13%/25                                                              10        33%/75                                                                             12    --     --     I/120                                                13%/25                                                              11A       6.5  0.025 --     --     I                                          11B       7.9  0.040 --     --     I                                          11C       3.3  I     --     --     17%/120                                                                       43%/240                                    12A       2.5  I     --     --     56                                         12B       1.4  26%/10(i.p.)                                                                        --     0.70   15%/60(i.p.)                               12C       93%/75                                                                             0.0034                                                                              --     --     I                                                    13%/25                                                              12D(base) 0.023                                                                              0.050 0.034  0.024  --                                         12D(HCl)  --   --    --     1.0(p.o)                                                                             --                                         12E       22   0.032 --     I/100  I/120                                      12F       14   0.020 --     I/50   I/120                                      13B       1.6  I     --     --     22%/120                                                                       72%/60                                                                        72%/30                                     15        2.0  0.060 --     --     I/120                                      16A       7%/75                                                                              I     --     --     I                                                    13%/25                                                              16B       7%/75                                                                              I     --     --     --                                                   20%/25                                                              17V       5.0  I/80  --     4.7    12%/60                                                                        42%/120                                                                       28%/240                                    17W       4.7  I/40  --     --     100                                        17AB      2.1  I/1.0,10,80                                                                         --     --     16                                         17AE      1.1  I/80  --     --     36%/60                                     17AF      0.88 I/80  --     --     26%/120                                                                       33%/120(i.p.)                              18        0.23 I/10                2.7                                        22        4.3  6.8   --     8.3    I/120,240                                  23        0.38 43-63%/                                                                             --     0.17   I/120                                                     0.001-0.1                                                      __________________________________________________________________________     (a)0.098 mg./kg. vs. morphine                                            

The compound of Example 2P has also been found to be active in thephenazocine tail flick antagonist test, the ED₅₀ (subcutaneousadministration) for that species being 7.8 mg./kg.

In the tail flick antagonist test, the 50% effective Antagonist Doses(AD_(50's)) of the narcotic antagonists, nalorphine and naloxone, aresimilar versus equi-agonist doses of the narcotics, morphine, meperidineand phenazocine. It has been shown that the AD₅₀ values of nalorphineand naloxone are about four times higher versus the compound of Example2M (the methanesulfonate) than they are versus an equi-agonist dose ofmorphine. This is considered to be an indication of differences in thereceptor-combining properties of the drugs. Determination of theAD_(50's) of nalorphine or naloxone versus the higher homologs of thecompound of Example 2M, namely the species of Examples 2C, 2D and 9Kmight categorize these latter species as being similar to morphine, anddifferent from the compound of Example 2M, or vice versa.

I claim:
 1. A compound having the formula ##STR48## where R₁ ishydrogen, lower-alkyl, lower-alkanoyl (only when R₄ is hydrogen),lower-alkenyl, lower-alkynyl, halo-lower-alkenyl, cyclo-lower-alkyl,cyclo-lower-alkyl-lower-alkyl, 2- or 3-furylmethyl, or such 2- or3-furylmethyl substituted on the unsubstituted ring carbon atoms by fromone to three methyl groups, phenyl-lower-alkyl, or phenyl-lower-alkylsubstituted in the phenyl ring by from one or two members of the groupconsisting of halogen, lower-alkyl, hydroxy, lower-alkanoyloxy,lower-alkoxy, lower-alkylmercapto, trifluoromethyl, amino,lower-alkanoylamino or a single methylenedioxy attached to adjacentcarbon atoms; R₂, R₂ ', R₂ " and R₂ "' are each hydrogen, or three ofthem are hydrogen and the fourth is halogen, lower-alkyl, hydroxy,loweralkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl,nitro, amino, lower-alkanoylamino, lower-alkoxycarbonylamino or phenyl,or two of the adjacent such groups together are methylenedioxy; R₃ ishydrogen or lower-alkyl; R₄ is hydrogen, lower-alkyl,lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl,lower-alkylthio-lower-alkyl, lower-alkylsulfinyl-lower-alkyl,phenylthio-lower-alkyl, phenylsulfinyl-lower-alkyl, lower-alkenyl orhalo-lower-alkyl, or R₃ and R₄ together are divalent lower-alkylene,--(CH₂)_(n) --, where n is one of the integers 3 or 4; and Z is thegroup ##STR49## where either R₅ and R₆ are both lower-alkyl or one ishydrogen and the other is lower-alkyl, or a group of the formula##STR50## where R₅ and R₆ are the same or different hydrogen,lower-alkyl, cyclo-lower-alkyl-lower-alkyl, phenyl orphenyl-lower-alkyl; R₇ is hydrogen, lower-alkanoyl, benzoyl or benzoylsubstituted by from one to three members of the group consisting oflower-alkyl, lower-alkoxy, hydroxy, halo or trifluoromethyl; and R₈ ishydrogen or lower-alkyl; or an acid-addition salt thereof.
 2. A compoundhaving the formula ##STR51## where R₁ is hydrogen, lower-alkyl,lower-alkenyl, lower-alkynyl, halo-lower-alkenyl,cyclo-lower-alkyl-lower-alkyl, 2- or 3-furyl methyl, or such 2- or3-furylmethyl substituted on the unsubstituted ring carbon atoms by fromone to three methyl groups, or phenyl-lower-alkyl; R₂ is hydrogen,hydroxy or lower-alkoxy; R₃ is hydrogen or lower-alkyl; R₄ islower-alkyl or lower-alkoxy-lower-alkyl, or R₃ and R₄ together aredivalent lower-alkylene, --(CH₂)_(n) --, where n is one of the integers3 or 4; Z is the group ##STR52## where either R₅ and R₆ are bothlower-alkyl or one is hydrogen and the other is lower-alkyl, or a groupof the formula: ##STR53## where R₅ and R₆ are the same or differenthydrogen, lower-alkyl, cyclo-lower-alkyl-lower-alkyl, phenyl orphenyl-lower-alkyl; or an acid-addition salt thereof.
 3. A compoundaccording to claim 2 where Z is the group ##STR54##
 4. A compoundaccording to claim 2 where Z is the group ##STR55## 5.3-Benzyl-6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-2-butenyl)-2,6-methano-3-benzazocineaccording to claim
 3. 6.3-Methyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocineaccording to claim
 4. 7.3-Methyl-6(eq)-ethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocineaccording to claim
 4. 8.3-Cyclopropylmethyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocineaccording to claim
 4. 9.3-Cyclopropylmethyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocineaccording to claim
 4. 10.3,6(eq)-Dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocineaccording to claim
 4. 11.3,6(eq)-Dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxyheptyl)-2,6-methano-3-benzazocineaccording to claim
 4. 12.3-Cyclopropylmethyl-6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxyheptyl)-2,6-methano-3-benzazocineaccording to claim
 4. 13. 3-Cyclopropylmethyl-6(eq)-methyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocineaccording to claim
 4. 14.3,6(eq)-Dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocineaccording to claim
 4. 15.3,6(eq)-Dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocineaccording to claim
 4. 16.3,6(eq)-Dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylhexyl)-2,6-methano-3-benzazocineaccording to claim
 4. 17.3-Cyclopropylmethyl-6(eq)-methyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylhexyl)-2,6-methano-3-benzazocineaccording to claim
 4. 18.3-Cyclopropylmethyl-6(eq)-methyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocineaccording to claim
 4. 19.3,6(eq)-Dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxyoctyl)-2,6-methano-3-benzazocineaccording to claim
 4. 20.3,6(eq)-Dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylpentyl)-2,6-methano-3-benzazocineaccording to claim
 4. 21. The process for preparing a compound accordingto claim 1 having the formula ##STR56## where R₁ is hydrogen,lower-alkyl, lower-alkanoyl (only when R₄ is hydrogen), lower-alkenyl,lower-alkynyl, halo-lower-alkenyl, cyclo-lower-alkyl,cyclo-lower-alkyl-lower-alkyl, 2- or 3-furylmethyl, or such 2- or3-furylmethyl substituted on the unsubstituted ring carbon atoms by fromone to three methyl groups, phenyl-lower-alkyl, or phenyl-lower-alkylsubstituted in the phenyl ring by from one or two members of the groupconsisting of halogen, lower-alkyl, hydroxy, lower-alkanoyloxy,lower-alkoxy, lower-alkylmercapto, trifluoromethyl, amino,lower-alkanoylamino or a single methylenedioxy attached to adjacentcarbon atoms; R₂, R₂ ', R₂ " and R₂ "' are each hydrogen, or three ofthem are hydrogen and the fourth is halogen, lower-alkyl, hydroxy,lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl,nitro, amino, lower-alkanoylamino, lower-alkoxycarbonylamino or phenyl,or two of the adjacent such groups together are methylenedioxy; R₃ ishydrogen or lower-alkyl; R₄ is hydrogen, lower-alkyl,lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl,lower-alkylthio-lower-alkyl, lower-alkylsulfinyl-lower-alkyl,phenylthio-lower-alkyl, phenylsulfinyl-lower-alkyl, lower-alkenyl orhalo-lower-alkyl, or R₃ and R₄ together are divalent lower-alkylene,--(CH₂)_(n) --, where n is one of the integers 3 or 4; and Z is thegroup ##STR57## where R₅ and R₆ are the same or different hydrogen,lower-alkyl, cyclo-lower-alkyl-lower-alkyl, phenyl orphenyl-lower-alkyl, except that R₅ and R₆ are not both hydrogen; and R₈is hydrogen or lower-alkyl, which comprises heating, with formic acid inan inert organic solvent or with a benzyl-di-lower-alkylammonium ortri-lower-alkylammonium formate, a compound having the formula ##STR58##where Y is the group ##STR59## and R₁, R₂, R₂ ', R₂ ", R₂ "', R₃, R₄,R₅, R₆ and R₈ have the meanings given above.